Azaindole derivative having PGD2 receptor antagonistic activity

ABSTRACT

The present invention creates an azaindole derivative having DP receptor antagonistic activity and a pharmaceutical composition comprising the said compound as an active ingredient, and further providing a therapeutic agent for treating allergic diseases. 
     A compound of the general formula (I) 
     
       
         
         
             
             
         
       
         
         
           
             wherein the ring A is an aromatic carbocyclic ring etc.; the ring B is a 3- to 8-membered nitrogen-containing non-aromatic heterocyclic ring etc.; the formula of —X 1 ═X 2 —X 3 ═X 4 — is a formula of —C(R 1 )═C(R 2 )—C(R 3 )═N— etc.; R 1 , R 2 , R 3 , R 4  and R 5  are independently a hydrogen atom or a halogen atom etc.; R 6  is optionally substituted C1-C6 alkyloxy etc.; R 7  is independently a halogen atom etc.; R 8  is optionally substituted C1-C6 alkyl etc.; R 9  is carboxy etc.; M is sulfonyl etc.; Y is a single bond etc.; L 1 , L 2  and L 3  are a single bond or alkylene optionally containing one or two heteroatoms etc.; n is 0 etc.; q is 0 etc.; a pharmaceutically acceptable salt or hydrate thereof.

TECHNICAL FIELD

This invention relates to an azaindole derivative having DP receptorantagonistic activity and a medicinal use thereof.

BACKGROUND ART

Prostaglandin D2(PGD2) is a metabolic product of arachidonic acidthrough PGG2 and PGH2, and known to have various potent physiologicalactivities. For example, in non-patent literature 1 it is described thatPGD2 is involved in sleeping and secretion of hormones in centralnervous system, and in inhibiting activity of platelet aggregation,contraction of bronchial smooth muscle, vasodilation and constriction ofa blood vessel etc. in peripheral system. Moreover, PGD2 is consideredto be involved in forming pathological condition of an allergic diseasesuch as bronchial asthma since it is a major metabolic product ofarachidonic acid produced from a mast cell, and has a potentbronchoconstricting effect, causing an increase of blood vesselpermeability and migration of inflammatory cell such as an eosinophil.

A DP receptor (also called DP1 receptor) or CRTH2 receptor (also calledDP2 receptor) is known as a receptor of PGD2 but these are completelydifferent receptors. In Patent literatures 1-9 indole derivatives havinga DP receptor antagonistic activity is disclosed, and in Patentliteratures 10-21 indole derivatives having a CRTH2 receptorantagonistic activity is disclosed

Also, indole derivatives having inhibitory activity againstnoradrenaline re-uptake are disclosed in Patent literature 22.

Patent literature 1: WO 2005/056527 Pamphlet

Patent literature 2: WO 2004/111047 Pamphlet

Patent literature 3: WO 2004/103970 Pamphlet

Patent literature 4: WO 2004/039807 Pamphlet

Patent literature 5: WO 2003/062200 Pamphlet

Patent literature 6: WO 2002/094830 Pamphlet

Patent literature 7: WO 2001/079169 Pamphlet

Patent literature 8: WO 2003/022814 Pamphlet

Patent literature 9: WO 2003/022813 Pamphlet

Patent literature 10: WO 2003/097598 Pamphlet

Patent literature 11: WO 2003/097042 Pamphlet

Patent literature 12: WO 2005/019171 Pamphlet

Patent literature 13: WO 2004/106302 Pamphlet

Patent literature 14: WO 2004/007451 Pamphlet

Patent literature 15: WO 2003/101981 Pamphlet

Patent literature 16: WO 2003/101961 Pamphlet

Patent literature 17: WO 2003/066047 Pamphlet

Patent literature 18: WO 2005/040112 Pamphlet

Patent literature 19: WO 2005/040114 Pamphlet

Patent literature 20: WO 2005/044260 Pamphlet

Patent literature 21: GB 2407318A Pamphlet

Patent literature 22: WO 2005/019208 Pamphlet

Non-patent literature 1: Pharmacol. Review, Vol. 46, page 205-229 (1994)

DISCLOSURE OF INVENTION Problem to be Solved

The present invention provides a novel compound having DP receptorantagonistic activity and a pharmaceutical composition comprising thesaid compound as an active ingredient. The said pharmaceuticalcomposition is useful as a therapeutic agent for treating allergicdiseases.

Means for Solving Problem

The present inventors have found that the azaindole derivative shownbelow has a potent DP receptor antagonistic activity and thepharmaceutical composition comprising the said compound as an activeingredient is useful as a therapeutic agent for treating allergicdiseases.

The present invention relates to

1) a compound of the general formula (I):

wherein the ring A is an aromatic carbocyclic ring or an aromaticheterocyclic ring;

the ring B is a 3- to 8-membered nitrogen-containing non-aromaticheterocyclic ring or a 3- to 8-membered nitrogen-containing aromaticheterocyclic ring;

the formula of —X¹═X²—X³═X⁴— is a formula of —N═C(R²)—C(R³)═C(R⁴)—,—C(R¹)═N—C(R³)═C(R⁴)—, —C(R¹)═C(R²)—N═C(R⁴)— or —C(R¹)═C(R²)—C(R³)═N—;

R¹, R², R³, R⁴ and R⁵ are independently a hydrogen atom, a halogen atom,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cyloalkyl, optionallysubstituted cyloalkenyl, hydroxy, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted cycloalkyloxy, optionally substitutedcycloalkenyloxy, mercapto, optionally substituted alkylthio, optionallysubstituted alkenylthio, optionally substituted alkynylthio, optionallysubstituted alkylsulfinyl, optionally substituted alkynylsulfonyl,optionally substituted alkynylsulfonyloxy, optionally substitutedcycloalkylthio, optionally substituted cycloalkylsulfinyl, optionallysubstituted cycloalkylsulfonyl, optionally substitutedcycloalkylsulfonyloxy, optionally substituted cycloalkenylthio,optionally substituted cycloalkenylsulfinyl, optionally substitutedcycloalkenylsulfonyl, optionally substituted cycloalkenylsulfonyloxy,amino, acyl, optionally substituted alkyloxycarbonyl, optionallysubstituted alkenyloxycarbonyl, optionally substitutedalkynyloxycarbonyl, optionally substituted carbamoyl, optionallysubstituted sulfamoyl, cyano, nitro, optionally substituted aryl,optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfinyl, optionally substituted arylsulfony,optionally substituted arylsulfonyoxy, optionally substitutedheteroaryl, optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or an optionally substituted non-aromaticheterocyclic group;

R⁶ is a hydrogen atom, optionally substituted C1-C6 alkyloxy, optionallysubstituted C2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy,optionally substituted C3-C6 cycloalkyloxy, optionally substituted C3-C6cycloalkenyloxy, optionally substituted aryloxy, optionally substitutedheteroaryloxy, optionally substituted C1-C6 alkylthio, optionallysubstituted C2-C6 alkenylthio, optionally substituted C2-C6 alkynylthio,optionally substituted C3-C6 cycloalkylthio, optionally substitutedC3-C6 cycloalkenylthio, optionally substituted arylthio, or optionallysubstituted heteroarylthio;

R⁷ is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted cycloalkenyl,hydroxy, optionally substituted alkyloxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedcycloalkyloxy, optionally substituted cycloalkenyloxy, mercapto,optionally substituted alkylthio, optionally substituted alkenylthio,optionally substituted alkynylthio, optionally substitutedalkylsulfinyl, optionally substituted alkylsulfonyl, optionallysubstituted alkylsulfonyloxy, optionally substituted cycloalkylthio,optionally substituted cycloalkylsulfinyl, optionally substitutedcycloalkylsulfonyl, optionally substituted cycloalkylsulfonyloxy,optionally substituted cycloalkenylthio, optionally substitutedcycloalkenylsulfinyl, optionally substituted cycloalkenylsulfonyl,optionally substituted cycloalkenylsulfonyloxy, optionally substitutedamino, acyl, optionally substituted alkyloxycarbonyl, optionallysubstituted alkenyloxycarbonyl, optionally substitutedalkynyloxycarbonyl, optionally substituted carbamoyl, optionallysubstituted sulfamoyl, cyano, nitro, optionally substituted aryl,optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfinyl, optionally substitutedarylsulfonyl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, optionallysubstituted heteroarylthio, optionally substituted heteroarylsulfinyl,optionally substituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or optionally substituted non-aromaticheterocyclic group;

R⁸ is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, optionally substituted alkyloxy, oxo,optionally substituted aryl, optionally substituted heteroaryl oroptionally substituted non-aromatic heterocyclic group;

R⁹ is carboxy, optionally substituted alkyloxycarbonyl, optionallysubstituted carbamoyl or carboxy equivalent;

M is carbonyl or sulfonyl;

Y is a single bond, optionally substituted alkylene optionallycontaining one or two heteroatom(s), an oxygen atom, a sulfur atom or—N(R¹⁰)—;

L¹, L² and L³ are independently a single bond, optionally substitutedalkylene optionally containing one or two heteroatom(s), optionallysubstituted alkenylene optionally containing one or two heteroatom(s),optionally substituted alkynylene optionally containing one or twoheteroatom(s) or —N(R¹¹)—;

R¹⁰ and R¹¹ are independently a hydrogen atom, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cycloalkyl, acyl, optionally substitutedalkyloxy, optionally substituted aryl, optionally substitutedheteroaryl, or optionally substituted non-aromatic heterocyclic group;

n is 0, 1 or 2; and

q is 0, 1, 2 or 3;

a pharmaceutically acceptable salt or hydrate thereof,

2) a compound of 1) wherein the formula of —X¹═X²—X³═X⁴— is a formula of—N═C(R²)—C(R³)═C(R⁴)—, a pharmaceutically acceptable salt or hydratethereof,

3) a compound of 1) wherein the formula of —X¹═X²—X³═X⁴— is a formula of—C(R¹)═N—C(R³)═C(R⁴)—, a pharmaceutically acceptable salt or hydratethereof,

4) a compound of 1) wherein the formula of —X¹═X²—X³═X⁴— is a formula of—C(R¹)═C(R²)—N═C(R⁴)—, a pharmaceutically acceptable salt or hydratethereof,

5) a compound of 1) wherein the formula of —X¹═X²—X³═X⁴— is a formula of—C(R¹)═C(R²)—C(R³)═N—, a pharmaceutically acceptable salt or hydratethereof,

6) a compounds of any of 1) to 5) wherein R⁶ is optionally substitutedC1-C6 alkyloxy, optionally substituted C1-C6 alkylthio, optionallysubstituted C3-C6 cycloalkyloxy, optionally substituted C3-C6cycloalkylthio, optionally substituted aryloxy or optionally substitutedarylthio, a pharmaceutically acceptable salt or hydrate thereof,7) a compound of any of 1) to 6) wherein the ring A is a benzene orpyridine ring, a pharmaceutically acceptable salt or hydrate thereof,8) a compound of any of 1) to 7) wherein R⁵ is a hydrogen atom, ahalogen atom, optionally substituted alkyl or optionally substitutedaryl, a pharmaceutically acceptable salt or hydrate thereof,9) a compound of any of 1) to 8) wherein Y is a single bond oroptionally substituted alkylene optionally containing one or twoheteroatom(s), a pharmaceutically acceptable salt or hydrate thereof,10) a compound of any of 1) to 9), wherein R⁹ is carboxy and L³ isoptionally substituted alkylene optionally containing one or twoheteroatom(s), pharmaceutically acceptable salt or hydrate thereof,11) a compound of any of 1) to 10) wherein M is sulfonyl, apharmaceutically acceptable salt or hydrate thereof,12) a compound of any of 1) to 12) wherein L¹ and L² is a single bond,the ring B is a formula of

and n is 0,

a pharmaceutically acceptable salt or hydrate thereof;

13) a compound of the general formula (II):

wherein the ring C is a ring of the formula of

the formula of —X¹═X²—X³═X⁴— is a formula of —N═C(R²)—C(R³)═C(R⁴)—,—C(R¹)═N—C(R³)═C(R⁴)—, —C(R¹)═C(R²)—N═C(R⁴)— or —C(R¹)═C(R²)—C(R³)═N—;

R¹, R², R³, R⁴ and R⁵ are independently a hydrogen atom, halogen atom,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, hydroxy, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted cycloalkyloxy, optionally substitutedcycloalkenyloxy, mercapto, optionally substituted alkylthio, optionallysubstituted alkenylthio, optionally substituted alkynylthio, optionallysubstituted alkylsulfinyl, optionally substituted alkylsulfonyl,optionally substituted alkylsulfonyloxy, optionally substitutedcycloalkylthio, optionally substituted cycloalkylsulfinyl, optionallysubstituted cycloalkylsulfonyl, optionally substitutedcycloalkylsulfonyloxy, optionally substituted cycloalkenylthio,optionally substituted cycloalkenylsulfinyl, optionally substitutedcycloalkenylsulfonyl, optionally substituted cycloalkenylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted carbamoyl,optionally substituted sulfamoyl, cyano, nitro, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfinyl, optionally substitutedarylsulfonyl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, optionallysubstituted heteroarylthio, optionally substituted heteroarylsulfinyl,optionally substituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or optionally substituted non-aromaticheterocyclic group;

R¹² is optionally substituted C1-C6 alkyloxy, optionally substitutedC2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionallysubstituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio,optionally substituted C2-C6 alkynylthio, optionally substituted C3-C6cycloalkyloxy, optionally substituted C3-C6 cycloalkylthio, optionallysubstituted aryloxy or optionally substituted arylthio;

R¹³ is independently a halogen atom, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedcarbamoyl, optionally substituted sulfamoyl, cyano, nitro, optionallysubstituted aryl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl or optionally substituted non-aromaticheterocyclic group;

R¹⁴ is independently optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, oxo, optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted non-aromatic heterocyclic group;

M is carbonyl or sulfoyl;

Y and L⁴ are independently a single bond or optionally substitutedalkylene optionally containing one or two heteroatom(s);

Z is CH, C(R¹³) or N;

n is 0, 1 or 2; and

q is 0, 1, 2 or 3;

a pharmaceutically acceptable salt or hydrate thereof,

14) a compound of 13) wherein the formula of —X¹═X²—X³═X⁴— is a formulaof —C(R¹)═N—C(R³)═C(R⁴)—, a pharmaceutically acceptable salt or hydratethereof,

15) a compound of 13) wherein the formula of —X¹═X²—X³═X⁴— is a formulaof —C(R¹)═C(R²)—N═C(R⁴)—, a pharmaceutically acceptable salt or hydratethereof,

16) a compound of 13) wherein the formula of —X¹═X²—X³═X⁴— is a formulaof —C(R¹)═C(R²)—C(R³)═N—, a pharmaceutically acceptable salt or hydratethereof,

17) a compound of 13) or 16) wherein R¹, R² and R⁵ are independently ahydrogen atom, a halogen atom or optionally substituted alkyl, apharmaceutically acceptable salt or hydrate thereof,

18) a compound of 17) wherein R¹, R² and R⁵ are hydrogen atoms, apharmaceutically acceptable salt or hydrate thereof,

19) a compound of any of 13) to 18) wherein R³ is a hydrogen atom, ahalogen atom, optionally substituted alkyl, optionally substitutedalkyloxy, optionally substituted amino, optionally substitutedcarbamoyl, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted non-aromatic heterocyclic group,

a pharmaceutically acceptable salt or hydrate thereof,

20) a compound of any of 13) or 16) to 19) wherein R³ is a hydrogenatom, a halogen atom, optionally substituted alkyloxy, optionallysubstituted amino, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted non-aromatic heterocyclic group;

a pharmaceutically acceptable salt or hydrate thereof,

21) a compound of any of 13) to 20) wherein R¹² is optionallysubstituted C1-C6 alkyl or optionally substituted C1-C6 alkylthio;

a pharmaceutically acceptable salt or hydrate thereof,

22) a compound of any of 13) to 21) wherein R¹³ is a halogen atom oroptionally substituted alkyl and q is 0 or 1;

a pharmaceutically acceptable salt or hydrate thereof,

23) a compound of any of 13) to 22) wherein M is sulfonyl, apharmaceutically acceptable salt or hydrate thereof,

24) a compound of any of 13) to 23) wherein R¹⁴ is alkyl and n is 0 or1, a pharmaceutically acceptable salt or hydrate thereof,

25) a compound of any of 13) to 24) wherein Y is a single bond oroptionally substituted alkylene, a pharmaceutically acceptable salt orhydrate thereof,

26) a compound of any of 13) to 25) wherein L⁴ is optionally substitutedalkylene, a pharmaceutically acceptable salt or hydrate thereof,

27) a compound of the general formula (III):

wherein the ring D is a formula of

R¹⁵, R¹⁶ and R¹⁸ are independently a hydrogen atom, a halogen atom,optionally substituted alkyl, optionally substituted alkyloxy,optionally substituted alkylthio, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, optionally substituted amino,cyano, nitro, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted non-aromatic heterocyclic group;

R¹⁷ is a hydrogen atom, a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cyloalkyl, optionally substituted cyloalkenyl,hydroxy, optionally substituted alkyloxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, mercapto, optionallysubstituted alkylthio, optionally substituted alkenylthio, optionallysubstituted alkynylthio, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, optionally substitutedalkylsulfonyloxy, optionally substituted amino, acyl, optionallysubstituted alkyloxycarbonyl, optionally substituted alkenyloxycarbonyl,optionally substituted alkynyloxycarbonyl, optionally substitutedcarbamoyl, optionally substituted sulfamoyl, cyano, nitro, optionallysubstituted aryl, optionally substituted aryloxy, optionally substitutedarylthio, optionally substituted arylsulfinyl, optionally substitutedarylsulfonyl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, optionallysubstituted heteroarylthio, optionally substituted heteroarylsulfinyl,optionally substituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or an optionally substituted non-aromaticheterocyclic group;

R¹⁹ is optionally substituted C1-C6 alkyloxy, optionally substitutedC2-C6 alkenyloxy, optionally substituted C2-C6 alkynyloxy, optionallysubstituted C1-C6 alkylthio, optionally substituted C2-C6 alkenylthio,optionally substituted C2-C6 alkynylthio, optionally substituted C3-C6cycloalkyloxy, optionally substituted C3-C6 cycloalkyltho, optionallysubstituted aryloxy or optionally substituted arylthio;

R²⁰ is independently a halogen atom, optionally substituted alkyl,optionally substituted cyloalkyl, optionally substituted amino,optionally substituted alkyloxycarbonyl, optionally substitutedcarbamoyl, optionally substituted sulfamoyl, cyano, nitro, optionallysubstituted aryl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl or an optionally substituted non-aromaticheterocyclic group;

R²¹ is independently optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, oxo, optionallysubstituted aryl, optionally substituted heteroaryl, or an optionallysubstituted non-aromatic heterocyclic group;

M is carbonyl or sulfonyl;

Z is CH, C(R²⁰), or N;

n is 0, 1 or 2 and

q is 0, 1, 2 or 3;

a pharmaceutically acceptable salt or hydrate thereof,

28) a compound of 27) wherein R¹⁷ is a hydrogen atom, a halogen atom,optionally substituted alkyl, optionally substituted alkyloxy,optionally substituted amino, optionally substituted carbamoyl,optionally substituted aryl, optionally substituted heteroaryl oroptionally substituted non-aromatic heterocyclic group;

a pharmaceutically acceptable salt or hydrate thereof,

29) a compound of 27) or 28) wherein R¹⁷ is a hydrogen atom, a halogenatom, optionally substituted alkyloxy, optionally substituted amino,optionally substituted aryl, optionally substituted heteroaryl oroptionally substituted non-aromatic heterocyclic group;

a pharmaceutically acceptable salt or hydrate thereof,

30) a compound of any of 27) to 29) wherein R¹⁵, R¹⁶ and R¹⁸ arehydrogen atoms, a pharmaceutically acceptable salt or hydrate thereof,

31) a compound of any of 27) to 30) wherein R¹⁹ is optionallysubstituted C1-C6 alkyl or optionally substituted C1-C6 alkylthio, apharmaceutically acceptable salt or hydrate thereof,

32) a compound of any of 27) to 31) wherein R²⁰ is optionallysubstituted alkyl or optionally substituted alkyloxy and q is 0 or 1, apharmaceutically acceptable salt or hydrate thereof,

33) a compound of any of 27) to 32) wherein M is sulfonyl, apharmaceutically acceptable salt or hydrate thereof,

34) a compound of any of 27) to 33) wherein the ring D is a formula of

a pharmaceutically acceptable salt or hydrate thereof,

35) a compound of any of 27) to 34) wherein n is 0, a pharmaceuticallyacceptable salt or hydrate thereof,

36) a pharmaceutical composition comprising the compound of any of 1) to35), pharmaceutically acceptable salt or hydrate thereof,

37) a pharmaceutical composition of 36) which is a DP receptorantagonist;

38) a pharmaceutical composition of 36) which is a therapeutic agent forallergy,

39) a pharmaceutical composition of 38) wherein the therapeutic agentfor allergy is a medicine for asthma,

40) a method for treating a disease related to DP receptor characterizedby administration of the compound of any of 1) to 35), pharmaceuticallyacceptable salt or hydrate thereof,

41) a method of 40) wherein the disease related to DP receptor isasthma,

42) use of the compound of any of 1) to 35), pharmaceutically acceptablesalt or hydrate thereof, in the manufacturing of a therapeutic agent fortreating diseases related to DP receptor,

43) use of the compound of 42), pharmaceutically acceptable salt orhydrate thereof wherein the disease related to DP receptor is asthma,

44) a compound of the general formula:

wherein R²² and R²³ are independently a hydrogen atom, a halogen atom,optionally substituted alkyl or optionally substituted aryl oroptionally substituted heteroaryl;

R²⁴ is optionally substituted alkoxy, optionally substituted alkylthio,optionally substituted carbamoyl or optionally substituted non-aromaticheterocyclic group;

a pharmaceutically acceptable salt or hydrate thereof, and

45) a compound of 44) wherein R²³ is optionally substituted alkoxy, apharmaceutically acceptable salt or hydrate thereof.

The present invention also includes the following inventions;

(1) a compound of the general formula (I-b):

wherein the ring A2 is an aromatic carbocyclic ring or an aromaticheterocyclic ring;

the ring B2 is a 3- to 8-membered nitrogen-containing heterocyclic ringcontaining only nitrogen atom as a heteroatom;

the formula of —X⁵═X⁶—X⁷═X⁸— is a formula of—N═C(R^(23b))—C(R^(23c))═C(R^(23d))—,—C(R^(23a))═N—C(R^(23c))═C(R^(23d))—,—C(R^(23a))═C(R^(23b))—N═C(R^(23d))— or—C(R^(23a))═C(R^(23b))—C(R^(23c))═N—;

R^(23a), R^(23b), R^(23c), and R^(23d) are independently a hydrogenatom, a halogen atom, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted cyloalkyl, optionally substituted alkyloxy, optionallysubstituted alkenyloxy, optionally substituted alkynyloxy, optionallysubstituted alkylthio, optionally substituted alkenylthio, optionallysubstituted alkynylthio, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, optionally substitutedalkylsulfonyloxy, amino, acyl, optionally substituted alkyloxycarbonyl,optionally substituted alkenyloxycarbonyl, optionally substitutedalkynyloxycarbonyl, optionally substituted carbamoyl cyano, nitro,optionally substituted aryl, optionally substituted aryloxy, optionallysubstituted arylthio, optionally substituted arylsulfinyl, optionallysubstituted arylsulfony, optionally substituted arylsulfonyoxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,optionally substituted heteroarylthio, optionally substitutedheteroarylsulfinyl, optionally substituted heteroarylsulfonyl,optionally substituted heteroarylsulfonyloxy, or an optionallysubstituted non-aromatic heterocyclic group;

R²⁴ is a hydrogen atom, a halogen atom, optionally substituted alkyl,acyl, optionally substituted aryl or optionally substituted heteroaryl;

R²⁵ is a hydrogen atom, optionally substituted C1-C6 alkyloxy,optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6alkynyloxy, optionally substituted C3-C6 cycloalkyloxy, optionallysubstituted C3-C6 cycloalkylmethyloxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C1-C6alkylthio, optionally substituted. C2-C6 alkenylthio, optionallysubstituted C2-C6 alkynylthio, optionally substituted C3-C6cycloalkylthio, optionally substituted C3-C6 cycloalkylmethylthio,optionally substituted arylthio or optionally substitutedheteroarylthio;

R²⁶ is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cyloalkyl, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted alkylthio, optionally substituted alkenylthio,optionally substituted alkynylthio, optionally substitutedalkylsulfinyl, optionally substituted alkylsulfonyl, optionallysubstituted alkylsulfonyloxy, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedalkenyloxycarbonyl, optionally substituted alkynyloxycarbonyl,optionally substituted carbamoyl, cyano, nitro, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfinyl, optionally substituted arylsulfony,optionally substituted arylsulfonyoxy, optionally substitutedheteroaryl, optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or an optionally substituted non-aromaticheterocyclic group;

R²⁷ is independently C1-C4 alkyl;

R²⁸ is a hydrogen atom, a halogen atom or C1-C4 alkyl;

Yb is a single bond or optionally substituted C1-C2 alkylene;

nb is 0, 1 or 2; and

qb is 0, 1 or 2;

a pharmaceutically acceptable salt or hydrate thereof,

(2) a compound of (1) wherein the formula of —X⁵═X⁶—X⁷═X⁸— is a formulaof —N═C(R^(23b))—C(R^(23c))═C(R^(23d))—, a pharmaceutically acceptablesalt or hydrate thereof,

(3) a compound of (1) wherein the formula of —X⁵═X⁶—X⁷═X⁸— is a formulaof —C(R^(23a))═N—C(R^(23c))═C(R^(23d))—, a pharmaceutically acceptablesalt or hydrate thereof,

(4) a compound of (1) wherein the formula of —X⁵═X⁶—X⁷═X⁸— is a formulaof —C(R^(23a))═C(R^(23b))—N═C(R^(23d))—, a pharmaceutically acceptablesalt or hydrate thereof,

(5) a compound of (1) wherein the formula of —X⁵═X⁶—X⁷═X⁸— is a formulaof —C(R^(23a))═C(R^(23b))—C(R^(23c))═N—, a pharmaceutically acceptablesalt or hydrate thereof,

(6) a compound of any of (1) to (5) wherein R²⁴ is a hydrogen atom, apharmaceutically acceptable salt or hydrate thereof,

(7) a compound of any of (1) to (6) wherein Yb is a single bond, apharmaceutically acceptable salt or hydrate thereof,

(8) a compound of any of (1) to (7) wherein the ring B2 is a formula of

and nb is 0, a pharmaceutically acceptable salt or hydrate thereof,(9) a compound of any of (1) to (8) wherein the ring A2 is a benzenering, R²⁵ is C2-C4 alkyloxy, C1-C4 alkyloxy substituted with a halogenatom, C2-C4 alkylthio, C1-C4 alkylthio substituted with a halogen atom,C3-C4 cycloalkyloxy, C3-C4 cycloalkylmethyloxy or optionally substitutedphenoxy;

a pharmaceutically acceptable salt or hydrate thereof,

(10) a compound of the general formula (II-b):

wherein the ring C2 is a formula of

the formula of —X⁵═X⁶—X⁷═X⁸— is a formula of—N═C(R^(23b))—C(R^(23c))═C(R^(23d))—,—C(R^(23a))═N—C(R^(23c))═C(R^(23d))—,—C(R^(23a))═C(R^(23b))—N═C(R^(23d))— or—C(R^(23a))═C(R^(23b))—C(R^(23c))═N—;

R^(23a), R^(23b), R^(23c) and R^(23d) are independently a hydrogen atom,a halogen atom, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcycloalkyl, optionally substituted alkyloxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedalkylthio, optionally substituted alkenylthio, optionally substitutedalkynylthio, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, optionally substituted alkylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted carbamoyl, cyano,nitro, optionally substituted aryl, optionally substituted aryloxy,optionally substituted arylthio, optionally substituted arylsulfinyl,optionally substituted arylsulfonyl, optionally substitutedarylsulfonyloxy, optionally substituted heteroaryl, optionallysubstituted heteroaryloxy, optionally substituted heteroarylthio,optionally substituted heteroarylsulfinyl, optionally substitutedheteroarylsulfonyl, optionally substituted heteroarylsulfonyloxy, oroptionally substituted non-aromatic heterocyclic group;

R²⁹ is C2-C4 alkyloxy, C1-C4 alkyloxy substituted with a halogen atom,C2-C4 alkylthio, C1-C4 alkylthio substituted with a halogen atom, C3-C4cycloalkyloxy, C3-C4 cycloalkylmethyloxy or optionally substitutedphenoxy;

R³⁰ is independently a halogen atom, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedcarbamoyl, cyano, nitro, optionally substituted aryl, optionallysubstituted arylsulfonyloxy, optionally substituted heteroaryl oroptionally substituted non-aromatic heterocyclic group;

Yb is a single bond or optionally substituted C1-C2 alkylene; and

qb is 0, 1 or 2;

a pharmaceutically acceptable salt or hydrate thereof,

(11) a compound of (10) wherein the formula of —X⁵═X⁶—X⁷═X⁸— is aformula of —C(R^(23a))═N—C(R^(23c))═C(R^(23d))—, a pharmaceuticallyacceptable salt or hydrate thereof,

(12) a compound of (10) wherein the formula of —X⁵═X⁶—X⁷═X⁸— is aformula of —C(R^(23a))═C(R^(23b))—N═C(R^(23d))—, a pharmaceuticallyacceptable salt or hydrate thereof,

(13) a compound of (1) wherein the formula of —X⁵═X⁶—X⁷═X⁸— is a formulaof —C(R^(23a))═C(R^(23b))—C(R^(23c))═N—, a pharmaceutically acceptablesalt or hydrate thereof,

(14) a compound of any of (10) to (13) wherein Yb is a single bond, apharmaceutically acceptable salt or hydrate thereof,

(15) a compound of any of (10) to (14) wherein R²⁹ is C2-C4 alkyloxy,C1-C4 alkyloxy substituted with a halogen atom, C2-C4 alkylthio or C1-C4alkylthio substituted with a halogen atom;

a pharmaceutically acceptable salt or hydrate thereof,

(16) a compound of the general formula (III-b):

wherein the ring D2 is a formula of

R³¹ and R³² are independently a hydrogen atom, a halogen atom,optionally substituted alkyl, optionally substituted alkyloxy,optionally substituted alkylthio, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, optionally substituted amino,cyano, nitro, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted non-aromatic heterocyclic group;

R³³ is a halogen atom, optionally substituted alkyl, optionallysubstituted alkenyl, optionally substituted alkynyl, optionallysubstituted cycloalkyl, optionally substituted alkyloxy, optionallysubstituted alkenyloxy, optionally substituted alkynyloxy, optionallysubstituted alkylthio, optionally substituted alkenylthio, optionallysubstituted alkynylthio, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, optionally substitutedalkylsulfonyloxy, optionally substituted amino, acyl, optionallysubstituted alkyloxycarbonyl, optionally substituted alkenyloxycarbonyl,optionally substituted alkynyloxycarbonyl, optionally substitutedcarbamoyl, cyano, nitro, optionally substituted aryl, optionallysubstituted aryloxy, optionally substituted arylthio, optionallysubstituted arylsulfinyl, optionally substituted arylsulfonyl,optionally substituted arylsulfonyloxy, optionally substitutedheteroaryl, optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or optionally substituted non-aromaticheterocyclic group;

R³⁴ is C2-C4 alkyloxy, C1-C4 alkyloxy substituted with a halogen atom,C2-C4 alkylthio, C1-C4 alkylthio substituted with a halogen atom, C3-C4cycloalkyloxy, C3-C4 cycloalkylmethyloxy or optionally substitutedphenoxy;

R³⁵ is a halogen atom, optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted amino, acyl, optionallysubstituted alkyloxycarbonyl, optionally substituted carbamoyl, cyano,nitro, optionally substituted aryl, optionally substitutedarylsulfonyloxy, optionally substituted heteroaryl or optionallysubstituted non-aromatic heterocyclic group; and

qb is 0, 1 or 2;

a pharmaceutically acceptable salt or hydrate thereof,

(17) a compound of (16) wherein R³¹ and R³² are hydrogen atoms, apharmaceutically acceptable salt or hydrate thereof,

(18) a compound of (16) or (17) wherein R³³ is a halogen atom,optionally substituted alkyloxy, optionally substituted amino,optionally substituted aryl or optionally substituted heteroaryl;

a pharmaceutically acceptable salt or hydrate thereof,

(19) a compound of any of (16) to (19) wherein the ring D2 is a formulaof

a pharmaceutically acceptable salt or hydrate thereof,

(20) a pharmaceutical composition comprising the compound of any of (1)to (19), pharmaceutically acceptable salt or hydrate thereof,

(21) a pharmaceutical composition of (20) which is a DP receptorantagonist,

(22) a pharmaceutical composition of (20) which is a therapeutic agentfor allergy,

(23) a pharmaceutical composition of (20) wherein the therapeutic agentfor allergy is a medicine for asthma,

(24) a method for treating a disease related to DP receptorcharacterized by administration of the compound of any of (1) to (19),pharmaceutically acceptable salt or hydrate thereof,

(25) a method of (24) wherein the disease related to DP receptor isasthma,

(26) use of the compound of any of (1) to (19), pharmaceuticallyacceptable salt or hydrate thereof, in the manufacturing of atherapeutic agent for treating diseases related to DP receptor, and

(27) use of the compound of (26), pharmaceutically acceptable salt orhydrate thereof wherein the disease related to DP receptor is asthma.

The present invention also includes the following inventions;

[1] a compound of the general formula (I-a):

wherein the ring A1 is an aromatic carbocyclic ring or an aromaticheterocyclic ring;

the ring B1 is a 5- or 6-membered nitrogen-containing heterocyclic ringcontaining only one nitrogen atom as a heteroatom;

the formula of —X^(a)═X^(b)—X^(c)═X^(d)— is a formula of—N═C(R^(b))—C(R^(c))═C(R^(d))—, —C(R^(a))═N—C(R^(c))═C(R^(d))—,—C(R^(a))═C(R^(b))—N═C(R^(d))— or —C(R^(a))═C(R^(b))—C(R^(c))═N—;

R^(a), R^(b), R^(c) and R^(d) are independently a hydrogen atom, ahalogen atom, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcyloalkyl, optionally substituted alkyloxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedalkylthio, optionally substituted alkenylthio, optionally substitutedalkynylthio, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, optionally substituted alkylsulfonyloxy,amino, acyl, optionally substituted alkyloxycarbonyl, optionallysubstituted alkenyloxycarbonyl, optionally substitutedalkynyloxycarbonyl, optionally substituted carbamoyl, cyano, nitro,optionally substituted aryl, optionally substituted aryloxy, optionallysubstituted arylthio, optionally substituted arylsulfinyl, optionallysubstituted arylsulfony, optionally substituted arylsulfonyoxy,optionally substituted heteroaryl, optionally substituted heteroaryloxy,optionally substituted heteroarylthio, optionally substitutedheteroarylsulfinyl, optionally substituted heteroarylsulfonyl,optionally substituted heteroarylsulfonyloxy, or an optionallysubstituted non-aromatic heterocyclic group;

R^(e) is a hydrogen atom, a halogen atom, optionally substituted alkyl,acyl, optionally substituted aryl or optionally substituted heteroaryl;

R^(f) is a hydrogen atom, optionally substituted C1-C6 alkyloxy,optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6alkynyloxy, optionally substituted C3-C6 cycloalkyloxy, optionallysubstituted C3-C6 cycloalkylmethyloxy, optionally substituted aryloxy,optionally substituted heteroaryloxy, optionally substituted C1-C6alkylthio, optionally substituted C2-C6 alkenylthio, optionallysubstituted C2-C6 alkynylthio, optionally substituted C3-C6cycloalkylthio, optionally substituted C3-C6 cycloalkylmethylthio,optionally substituted arylthio or optionally substitutedheteroarylthio;

R^(g) is independently a halogen atom, optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted cyloalkyl, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted alkylthio, optionally substituted alkenylthio,optionally substituted alkynylthio, optionally substitutedalkylsulfinyl, optionally substituted alkylsulfonyl, optionallysubstituted alkylsulfonyloxy, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedalkenyloxycarbonyl, optionally substituted alkynyloxycarbonyl,optionally substituted carbamoyl, cyano, nitro, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfinyl, optionally substituted arylsulfony,optionally substituted arylsulfonyoxy, optionally substitutedheteroaryl, optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or an optionally substituted non-aromaticheterocyclic group;

R^(h) is independently C1-C4 alkyl;

R^(j) is a hydrogen atom, a halogen atom or C1-C4 alkyl;

Ya is a single bond or optionally substituted C1-C2 alkylene;

na is 0, 1 or 2; and

qa is 0, 1 or 2;

a pharmaceutically acceptable salt or hydrate thereof,

[2] a compound of [1] wherein the formula of —X⁸═X^(b)—X^(c)═X^(d)— is aformula of —N═C(R^(b))—C(R^(c))═C(R^(d))—, a pharmaceutically acceptablesalt or hydrate thereof,

[3] a compound of [1] wherein the formula of —X^(a)═X^(b)—X^(c)═X^(d)-,is a formula of —C(R^(a))═N—C(R^(c))═C(R^(d))—, a pharmaceuticallyacceptable salt or hydrate thereof,

[4] a compound of [1] wherein the formula of —X^(a)═X^(b)—X^(c)═X^(d)-,is a formula of —C(R^(a))═C(R^(b))—N═C(R^(d))—, a pharmaceuticallyacceptable salt or hydrate thereof,

[5] a compound of [1] wherein the formula of —X^(a)═X^(b)—X^(c)═X^(d)—is a formula of —C(R^(a))═C(R^(b))—C(R^(c))═N—, a pharmaceuticallyacceptable salt or hydrate thereof,

[6] a compound of any of [1] to [5] wherein R^(e) is a hydrogen atom, apharmaceutically acceptable salt or hydrate thereof,

[7] a compound of any of [1] to [6] wherein Ya is a single bond, apharmaceutically acceptable salt or hydrate thereof,

[8] a compound of any of [1] to [7] wherein the ring B1 is a formula of

and na is 0;

a pharmaceutically acceptable salt or hydrate thereof,

[9] a compound of any of [1] to [8] wherein the ring A1 is a benzenering, R^(f) is C2-C4 alkyloxy, C1-C4 alkyloxy substituted with a halogenatom, C2-C4 alkylthio, C1-C4 alkylthio substituted with a halogen atom,C3-C4 cycloalkyloxy, C3-C4 cycloalkylmethyloxy or optionally substitutedphenoxy;

a pharmaceutically acceptable salt or hydrate thereof,

[10] a compound of the general formula (II-a):

wherein the ring C1 is a ring of the formula of

the formula of —X^(a)═X^(b)—X^(c)═X^(d)— is a formula of—N═C(R^(b))—C(R^(c))═C(R^(d))—, —C(R^(a))═N—C(R^(c))═C(R^(d))—,—C(R^(a))═C(R^(b))—N═C(R^(d))— or —C(R)═C(R^(b))—C(R^(c))═N—;

R^(a), R^(b), R^(c) and R^(d) are independently a hydrogen atom, ahalogen atom, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substitutedcyloalkyl, optionally substituted alkyloxy, optionally substitutedalkenyloxy, optionally substituted alkynyloxy, optionally substitutedalkylthio, optionally substituted alkenylthio, optionally substitutedalkynylthio, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, optionally substituted alkylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted carbamoyl, cyano,nitro, optionally substituted aryl, optionally substituted aryloxy,optionally substituted arylthio, optionally substituted arylsulfinyl,optionally substituted arylsulfony, optionally substitutedarylsulfonyoxy, optionally substituted heteroaryl, optionallysubstituted heteroaryloxy, optionally substituted heteroarylthio,optionally substituted heteroarylsulfinyl, optionally substitutedheteroarylsulfonyl, optionally substituted heteroarylsulfonyloxy, or anoptionally substituted non-aromatic heterocyclic group;

R^(j) is C2-C4 alkyloxy, C1-C4 alkyloxy substituted with a halogen atom,C2-C4 alkylthio, C1-C4 alkylthio substituted with a halogen atom, C3-C4cycloalkyloxy, C3-C4 cycloalkylmethyloxy or optionally substitutedphenoxy;

R^(k) is independently a halogen atom, optionally substituted alkyl,optionally substituted cycloalkyl, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedcarbamoyl, cyano, nitro, optionally substituted aryl, optionallysubstituted arylsulfonyloxy, optionally substituted heteroaryl oroptionally substituted non-aromatic heterocyclic group;

Ya is a single bond or optionally substituted C1-C2 alkylene; and

qa is 0, 1 or 2;

a pharmaceutically acceptable salt or hydrate thereof,

[11] a compound of [10] wherein the formula of —X^(a)═X^(b)—X^(c)═X^(d)—is a formula of —C(R^(a))═N—C(R^(c))═C(R^(d))—, a pharmaceuticallyacceptable salt or hydrate thereof,

[12] a compound of [10] wherein the formula of —X^(a)═X^(b)—X^(c)═X^(d)—is a formula of —C(R^(a))═C(R^(b))—N═C(R^(d))—, a pharmaceuticallyacceptable salt or hydrate thereof,

[13] a compound of [10] wherein the formula of —X^(a)═X^(b)—X^(c)═X^(d)—is a formula of —C(R^(a))═C(R^(b))—C(R^(c))═N—, a pharmaceuticallyacceptable salt or hydrate thereof,

[14] a compound of any of [10] to [13] wherein Ya is a single bond, apharmaceutically acceptable salt or hydrate thereof,

[15] a compound of any of [10] to [13] wherein Rj is C2-C4 alkyloxy,C1-C4 alkyloxy substituted with a halogen atom, C2-C4 alkylthio, C1-C4alkylthio substituted with a halogen atom;

a pharmaceutically acceptable salt or hydrate thereof,

[16] a pharmaceutical composition comprising the compound of any of [1]to [15], pharmaceutically acceptable salt or hydrate thereof,

[17] a pharmaceutical composition of [16] which is a therapeutic agentfor allergy,

[18] a pharmaceutical composition of [17] wherein the therapeutic agentfor allergy is a medicine for asthma,

[19] a method for treating a disease related to DP receptorcharacterized by administration of the compound of any of [1] to [15],pharmaceutically acceptable salt or hydrate thereof,

[20] a method of [19] wherein the disease related to DP receptor isasthma,

[21] use of the compound of any of [1] to [15], pharmaceuticallyacceptable salt or hydrate thereof, in the manufacturing of atherapeutic agent for treating diseases related to DP receptor, and

[22] use of the compound of [21], pharmaceutically acceptable salt orhydrate thereof wherein the disease related to DP receptor is asthma.

Terms herein used are explained below. In the present specification eachterm is used under the unified definition and has the same meaning whenused alone or in combination with other terms.

In the present specification, a term of “halogen atom” means a fluorineatom, a chlorine atom, a bromine atom and an iodine atom. A fluorineatom, a chlorine atom and a bromine atom are preferable.

In the present specification, a term of “hetero atom” means an oxygenatom, a sulfur atom and a nitrogen atom.

In the present specification, a term of “alkyl” means a monovalentstraight or branched hydrocarbon group having one to eight carbonatom(s). For example, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl,n-hexyl, isohexyl, n-heptyl, n-octyl and the like are exemplified. C1-C6alkyl is preferred. C1-C4 alkyl is further preferred. When a number ofcarbon is specified, it means “alkyl” having the carbon number withinthe range.

In the present specification, a term of “alkenyl” means a monovalentstraight or branched hydrocarbon group having two to eight carbon atomsand one or more double bond(s). For example, vinyl, allyl, 1-propenyl,2-butenyl, 2-pentenyl, 2-hexenyl, 2-heptenyl, 2-octenyl and the like areexemplified. C2-C6 alkenyl is preferred. Moreover, C2-C4 alkenyl isfurther preferred.

In the present specification, a term of “alkynyl” means a monovalentstraight or branched hydrocarbon group having two to eight carbon atomsand one or more triple bond(s). For example, ethynyl, 1-propynyl,2-propynyl, 2-butynyl, 2-pentynyl, 2-hexynyl, 2-heptynyl, 2-octynyl andthe like are exemplified. C2-C6 alkynyl is preferred. Moreover, C2-C4alkynyl is further preferred.

In the present specification, a term of “cycloalkyl” means a cycloalkylhaving three to eight carbon atoms and for example, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and thelike are exemplified. C3-C6 cycloalkyl is preferred.

In the present specification, a term of “cycloalkenyl” means acycloalkenyl having three to eight carbon atoms and for example,cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl,cycloocentyl and the like are exemplified. C3-C6 cycloalkenyl ispreferred.

In the present specification, a term of “alkyloxy” means a group whereinan oxygen atom is substituted with one “alkyl” above and for example,methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy,sec-butyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, 2-pentyloxy,3-pentyloxy, n-hexyloxy, isohexyloxy, 2-hexyloxy, 3-hexyloxy,n-heptyloxy, n-octyloxy, and the like are exemplified. C1-C6 alkyloxy ispreferred. Moreover, C1-C4 alkyloxy is further preferred. When a numberof carbon is specified, it means “alkyloxy” having the carbon numberwithin the range.

In the present specification, a term of “alkenyloxy” means a groupwherein an oxygen atom is substituted with one “alkenyl” above and forexample, vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy,2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like are exemplified.C2-C6 alkenyloxy is preferred. Moreover, C2-C4 alkenyloxy is furtherpreferred. When a number of carbon is specified, it means “alkenyloxy”having the carbon number within the range.

In the present specification, a term of “alkynyloxy” means a groupwherein an oxygen atom is substituted with one “alkynyl” above and forexample, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy,2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the likeare exemplified. C2-C6 alkynyloxy is preferred. Moreover, C2-C4alkynyloxy is further preferred. When a number of carbon is specified,it means “alkynyloxy” having the carbon number within the range.

In the present specification, a term of “cycloalkyloxy” means a groupwherein an oxygen atom is substituted with one “cycloalkyl” above andfor example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy and cyclooctyloxy are exemplified. C3-C6cycloalkyloxy is preferred. When a number of carbon is specified, itmeans “cycloalkyloxy” having the carbon number within the range.

In the present specification, a term of “cycloalkenyloxy” means a groupwherein an oxygen atom is substituted with one “cycloalkenyl” above andfor example, cyclopropenyloxy, cyclobutenyloxy, cyclopentenyloxy,cyclohexenyloxy, cycloheptenyloxy, and cyclooctenyloxy are exemplified.C3-C6 cycloalkenyloxy is preferred. When a number of carbon isspecified, it means “cycloalkenyloxy” having the carbon number withinthe range.

In the present specification, a term of “alkylthio” means a groupwherein a sulfur atom is substituted with one “alkyl” above, and forexample, methylthio, ethylthio, n-propylthio, isopropylthio,n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio,isopentylthio, 2-pentylthio, 3-pentylthio, n-hexylthio, isohexylthio,2-hexylthio, 3-hexylthio, n-heptylthio, n-octylthio, and the like areexemplified. C1-C6 Alkylthio is preferred. Moreover, C1-C4 alkylthio ismore preferred. When a number of carbon is specified, it means“alkylthio” having the carbon number within the range.

In the present specification, a term of “alkynylthio” means a groupwherein a sulfur atom is substituted with one “alkynyl” above and forexample, ethynylthio, 1-propynylthio, 2-propynylthio, 2-butynylthio,2-pentynylthio, 2-hexynylthio, 2-heptynylthio, 2-octynylthio and thelike are exemplified. C2-C6 alkynylthio is preferred. Moreover, C2-C4alkynylthio is further preferred. When a number of carbon is specified,it means “alkynylthio” having the carbon number within the range.

In the present specification, a term of “alkylsulfinyl” means a groupwherein sulfinyl is substituted with one “alkyl” above and for example,methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl,n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl,tert-butylsulfinyl, n-pentylsulfinyl, isopentylsulfinyl,2-pentylsulfinyl, 3-pentylsulfinyl, n-hexylsulfinyl, isohexylsulfinyl,2-hexylsulfinyl, 3-hexylsulfinyl, n-heptylsulfinyl, n-octylsulfinyl andthe like are exemplified. C1-C6 alkylsulfinyl is preferred. Moreover,C1-C4 alkylsulfinyl is further preferred.

In the present specification, a term of “alkylsulfonyl” means a groupwherein sulfonyl is substituted with one “alkyl” above and for example,methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl,n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl,2-pentylsulfonyl, 3-pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl,2-hexylsulfonyl, 3-hexylsulfonyl, n-heptylsulfonyl, n-octylsulfonyl andthe like are exemplified. C1-C6 alkylsulfonyl is preferred. Moreover,C1-C4 alkylsulfonyl is further preferred.

In the present specification, a term of “alkylsulfonyloxy” means a groupwherein an oxygen atom is substituted with one “alkylsulfonyl” above andfor example, methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy,isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy,sec-butylsulfonyloxy, tert-butylsulfonyloxy, n-pentylsulfonyloxy,isopentylsulfonyloxy, 2-pentylsulfonyloxy, 3-pentylsulfonyloxy,n-hexylsulfonyloxy, isohexylsulfonyloxy, 2-hexylsulfonyloxy,3-hexylsulfonyloxy, n-heptylsulfonyloxy, n-octylsulfonyloxy and the likeare exemplified. C1-C6 alkylsulfonyl is preferred. Moreover, C1-C4alkylsulfonyl is further preferred.

In the present specification, a term of “cycloalkylthio” means a groupwherein a sulfur atom is substituted with one “cycloalkyl” above and forexample, cyclopropylthio, cyclobutylthio, cyclopentylthio,cyclohexylthio, cycloheptylthio, cyclooctylthio and the like areexemplified. C3-C6 cycloalkylthio is preferred. When a number of carbonis specified, it means “cycloalkylthio” having the carbon number withinthe range.

In the present specification, a term of “cycloalkylsulfinyl” includes asubstituent group in which sulfinyl is substituted with one “cycloalkyl”above. For example, cyclopropylsulfinyl, cyclobutylsulfinyl,cyclopentylsulfinyl, cyclohexylsulfinyl, cycloheptylsulfinyl, andcyclooctylsulfinyl are exemplified. Preferably C3-C6 cycloalkylsulfinylis exemplified.

In the present specification, a term of “cycloalkylsulfonyl” includes asubstituent group in which sulfonyl is substituted with one “cycloalkyl”described. For example, cyclopropylsulfonyl, cyclobutylsulfonyl,cyclopentylsulfonyl, cyclohexylsulfonyl, cycloheptylsulfonyl, andcyclooctylsulfonyl are exemplified. Preferably C3-C6 cycloalkylsulfonylis exemplified.

In the present specification, a term of “cycloalkylsulfinyloxy” includesa substituent group in which an oxygen atom is substituted with one“cycloalkylsulfonyl” above. For example, cyclopropylsulfonyloxy,cyclobutylsulfonyloxy, cyclopentylsulfonyloxy, cyclohexylsulfonyloxy,cycloheptylsulfonyloxy, and cyclooctylsulfonyloxy are exemplified.Preferably C3-C6 cycloalkylsulfonyloxy is exemplified.

In the present specification, a term of “cycloalkenylthio” includes asubstituent group in which a sulfur atom is substituted with one“cycloalkenyl” above. For example, cyclopropenylthio, cyclobutenylthio,cyclopentenylthio, cyclohexenylthio, cycloheptenylthio, andcyclooctenylthio are exemplified. Preferably C3-C6 cycloalkenylthio isexemplified. When a number of carbon is specified, it means“cycloalkenylthio” having the carbon number within the range.

In the present specification, a term of “cycloalkenylsulfinyl” includesa substituent group in which sulfinyl is substituted with one“cycloalkenyl” above. For example, cyclopropenylsulfinyl,cyclobutenylsulfinyl, cyclopentenylsulfinyl, cyclohexenylsulfinyl,cycloheptenylsulfinyl, and cyclooctenylsulfinyl are exemplified.Preferably C3-C6 cycloalkenylsulfinyl is exemplified.

In the present specification, a term of “cycloalkenylsulfonyl” includesa substituent group in which sulfonyl is substituted with one“cycloalkenyl” above. For example, cyclopropenylsulfonyl,cyclobutenylsulfonyl, cyclopentenylsulfonyl, cyclohexenylsulfonyl,cycloheptenylsulfonyl, and cyclooctenylsulfonyl are exemplified.Preferably C3-C6 cycloalkenylsulfonyl is exemplified.

In the present specification, a term of “cycloalkenylsulfonyloxy”includes a substituent group in which an oxygen atom is substituted withone “cycloalkenylsulfonyl” above. For example, cyclopropenylsulfonyloxy,cyclobutenylsulfonyloxy, cyclopentenylsulfonyloxy,cyclohexenylsulfonyloxy, cycloheptenylsulfonyloxy, andcyclooctenylsulfonyloxy are exemplified. Preferably C3-C6cycloalkenylsulfonyloxy is exemplified.

In the present specification, a term of “alkyloxycarbonyl” includes asubstituent group in which carbonyl is substituted with one “alkyloxy”above. For example, methyloxycarbonyl, ethyloxycarbonyl,n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl,tert-butyloxycarbonyl and n-pentyloxycarbonyl are exemplified.Preferably C1-C2 alkyloxycarbonyl is exemplified.

In the present specification, a term of “alkenyloxycarbonyl” includes asubstituent group in which carbonyl is substituted with one “alkenyloxy”above. For example, vinyloxycarbonyl, allyloxycarbonyl,1-propenyloxycarbonyl, and 2-pentenyloxyarbonyl are exemplified.Preferably C2-C4 alkyloxycarbonyl is exemplified.

In the present specification, a term of “alkynyloxycarbonyl” includes asubstituent group in which carbonyl is substituted with one “alkynyloxy”above. For example, ethynyloxycarbonyl, 1-propynyloxycarbonyl,2-propynyloxycarbonyl, 2-butynyloxyarbonyl and 2-pentynyloxycarbonyl areexemplified. Preferably C2-C4 alkynyloxycarbonyl is exemplified.

In the present specification, a term of “acyl” includes alkylcarbonylwherein the part of alkyl is “alkyl” described before, alkenylcarbonylwherein the part of alkenyl is “alkenyl” described before,alkynylcarbonyl wherein the part of alkynyl is “alkynyl” describedbefore, cycloalkylcarbonyl wherein the part of cycloalkyl is“cycloalkyl” described before, arylcarbonyl wherein the part of aryl is“aryl” described below, heteroarylcarbonyl wherein the part ofheteroaryl is “heteroaryl” described below and non-aromaticheterocycliccarbonyl wherein the part of non-aromatic heterocyclic groupis “non-aromatic heterocyclic group” described below. “Alkyl”,“alkenyl”, “alkynyl”, “cycloalkyl”, “aryl”, “heteroaryl” and“non-aromatic heterocyclic” may be substituted respectively withsubstituent groups exemplified in “optionally substituted alkyl”,“optionally substituted alkenyl”, “optionally substituted alkynyl”,“optionally substituted cycloalkyl”, “optionally substituted aryl”,“optionally substituted heteroaryl” and “optionally substitutednon-aromatic heterocyclic group” described below. Examples of the acylgroup include acetyl, propionyl, butyroyl, cyclohexylcarbonyl, benzoyl,pyridinecarbonyl and the like.

In the present specification, a term of “optionally substituted amino”includes an amino group which may be substituted with one or twogroup(s) of “alkyl” before, “alkenyl” before, “alkynyl” before,“cycloalkyl” before, “cycloalkenyl” before, “aryl” below, “heteroaryl”below, “acyl” before, “alkyloxycarbonyl” before, “alkenyloxycarbonyl”before, “alkynyloxycarbonyl” before, “alkylsulfonyl”, “alkenylsulfonyl”,“alkynylsulfonyl”, “arylsulfonyl” and/or “heteroarylsulfonyl” before.Examples of the optionally substituted amino group include amino,methylamino, dimethylamino, ethylamino, diethylamino, ethylmethylamino,benzylamino, acetylamino, benzoylamino, methyloxycarbonylamino andmethanesulfonylamino. Preferably, amino, methylamino, dimethylamino,diethylamino, ethylmethylamino, acetylamino and methanesulfonylamino areexemplified.

In the present specification, a term of “optionally substitutedcarbamoyl” includes an aminocarbonyl group wherein the part ofoptionally substituted amino is “optionally substituted amino” describedbefore and examples of the optionally substituted carbamoyl groupincludes carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl,N-ethyl-N-methylcarbamoyl, N,N-diethylcarbamoyl, N-phenylcarbamoyl,N-benzylcarbamoyl, N-acetylcarbamoyl and N-methylsulfonylcarbamoyl etc.Preferably, carbamoyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl andN-methylsulfonylcarbamoyl etc. are exemplified.

In the present specification, a term of “optionally substitutedsulfamoyl” includes an aminosulfonyl group wherein the part ofoptionally substituted amino is “optionally substituted amino” describedbefore and examples of the optionally substituted sulfamoyl groupinclude sulfamoyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl,N-ethyl-N-methylsulfamoyl, N,N-diethylsulfamoyl, N-phenylsulfamoyl,N-benzylsulfamoyl, N-acetylsulfamoyl and N-methylsulfonylsulfamoyl etc.Preferably, sulfamoyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl andN-methylsulfonylsulfamoyl etc. are exemplified.

In the present specification, a term of “alkylene” includes a straightor branched alkylene group having one to eight carbon atom(s) and forexample, methylene, ethylene, 1-methylethylene, trimethylene,1-methyltrimethylene, pentamethylene, hexamethylene etc. areexemplified. C1-C4 alkylene is preferred. Moreover, C1-C2 alkylene isfurther preferred.

In the present specification, a term of “aryl” includes a monocyclic orfused cyclic aromatic hydrocarbons and it may be fused with “cycloalkyl”before, “cycloalkenyl” before or “non-aromatic heterocyclic group” belowat any possible position. Both of monocyclic ring and fused ring may besubstituted at any position and for example, phenyl, 1-naphthyl,2-naphthyl, anthryl, tetrahydronaphthyl, 1,3-benzodioxolyl,1,4-benzodioxanyl etc. are exemplified. Phenyl, 1-naphthyl and2-naphthyl are preferred. Moreover, phenyl is further preferred.

In the present specification, a term of “non-aromatic heterocyclicgroup” in R¹, R², R³, R⁴, R⁵, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ includes a 5- to7-membered non-aromatic heterocyclic ring containing one or more ofheteroatom(s) selected independently from oxygen, sulfur and nitrogenatoms or a multicyclic ring formed by fusing the two or more ringsthereof. For example, pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g.,2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl(e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g.,pyrazolinyl), piperidyl (e.g., piperidino, 2-piperidyl), piperadinyl(e.g., 1-piperadinyl), indolinyl (e.g., 1-indolinyl), isoindolinyl(e.g., isoindolinyl), morpholinyl (e.g., morpholino, 3-morpholinyl) etc.are exemplified.

In the present specification, a term of “non-aromatic heterocyclicgroup” in R⁷, R⁸, R¹⁰, R¹¹, R¹³, R¹⁴, R²⁰ and R²¹ includes a 5- to7-membered non-aromatic heterocyclic ring containing one or more ofheteroatom(s) selected independently from oxygen, sulfur and nitrogenatoms or a multicyclic ring formed by fusing the two or more ringsthereof. For example, pyrrolidinyl (e.g., 1-pyrrolidinyl,2-pyrrolidinyl), piperidyl (e.g., piperidino, 2-piperidyl), piperadinyl(e.g., 1-piperadinyl), morpholinyl (e.g., morpholino, 3-morpholinyl)etc. are exemplified.

In the present specification, a term of “heteroaryl” in R¹, R², R³, R⁴,R⁵, R¹⁵, R¹⁶, R¹⁷ and R¹⁸ includes a 5- to 6-membered aromatic ringcontaining one or more of heteroatom(s) selected independently fromoxygen, sulfur and nitrogen atoms and it may be fused with “cycloalkyl”before, “aryl” before, “non-aromatic heterocyclic group” or otherheteroaryl at any possible position. The heteroaryl group may besubstituted at any position whenever it is a monocyclic ring or a fusedring. For example, pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl),furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl),imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g.,1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl),isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl(e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl,4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl (e.g.,1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl(e.g., 1,3,4-thiadiazolyl), indolidinyl (e.g., 2-indolidinyl,6-indolidinyl), isoindolynyl (e.g., 2-isoindolynyl), indolyl (e.g.,1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), purinyl(e.g., 8-purinyl), quinolidinyl (e.g., 2-quinolidinyl), isoquinolyl(e.g., 3-isoquinolyl), quinolyl (e.g., 2-quinolyl, 5-quinolyl),phtharazinyl (e.g., 1-phtharazinyl), naphthylidinyl (e.g.,2-naphthylidinyl), quinolanyl (e.g., 2-quinolanyl), quinazolinyl (e.g.,2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g.,2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 4-carbazolyl),phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl(e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g.,1-dibenzofuranyl, 2-dibenzofuranyl), benzoimidazolyl (e.g.,2-benzoimidazolyl), benzoisoxazolyl (e.g., 3-benzoisoxazolyl),benzooxazolyl (e.g., 2-benzooxazolyl), benzooxadiazolyl (e.g.,4-benzooxadiazolyl), benzoisothiazolyl (e.g., 3-benzoisothiazolyl),benzothiazolyl (e.g., 2-benzothiazolyl), benzofuryl (e.g.,3-benzofuryl), benzothienyl (e.g., 2-benzothienyl), dibenzothienyl(e.g., 2-dibenzothienyl) and benzodioxolyl (e.g., 1,3-benzodioxolyl) areexemplified.

In the present specification, a term of “heteroaryl” in R⁷, R⁸, R¹⁰,R¹¹, R¹³, R¹⁴, R²⁰ and R²¹ includes a 5- to 6-membered aromatic ringcontaining one or more of heteroatom(s) selected independently fromoxygen, sulfur and nitrogen atoms and it may be fused with “cycloalkyl”before, “aryl” before, “non-aromatic heterocyclic group” before or otherheteroaryl at any possible position. The heteroaryl group may besubstituted at any position whenever it is monocyclic or fused ring. Forexample, furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl,3-thienyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl(e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl),isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl(e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl),pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl,4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), oxadiazolyl (e.g.,1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl),benzoimidazolyl (e.g., 2-benzoimidazolyl), benzoisoxazolyl (e.g.,3-benzoisoxazolyl), benzooxazolyl (e.g., 2-benzooxazolyl), benzofuryl(e.g., 3-benzofuryl), benzothienyl (e.g., 2-benzothienyl) areexemplified.

In the present specification, a term of “aryloxy” includes a substituentgroup in which an oxygen atom is substituted with one “aryl” above andfor example, phenyloxy and naphthyloxy etc. are exemplified.

In the present specification, a term of “arylthio” includes asubstituent group in which a sulfur atom is substituted with one “aryl”above and for example, phenylthio and naphthylthio etc. are exemplified.

In the present specification, a term of “arylsulfinyl” includes asubstituent group in which sulfinyl is substituted with one “aryl” aboveand for example, phenylsulfinyl and naphthylsulfinyl etc. areexemplified.

In the present specification, a term of “arylsulfonyl” includes asubstituent group in which sulfonyl is substituted with one “aryl” aboveand for example, phenylsulfonyl and naphthylsulfinyl etc. areexemplified.

In the present specification, examples of “arylsulfonyloxy includephenylsulfonyloxy and naphthylsulfonyloxy etc.

In the present specification, a term of “heteroaryloxy” includes asubstituent group in which an oxygen atom is substituted with one“heteroaryl” above. For example, pyrrolyloxy, furyloxy, thienyloxy,imidazolyloxy, pyrazolyloxy, isothiazolyloxy, isoxazolyloxy,oxazolyloxy, thiazolyloxy, pyridyloxy, pyrazinyloxy, pyrimidinyloxy,pyridazinyloxy, tetrazolyloxy, oxadiazolyloxy, thiadiazolyloxy,indolidinyloxy, isoindolynyloxy, indolyloxy, indazolyloxy, purinyloxy,quinolidinyloxy, isoquinolyloxy, quinolyloxy, phtharazinyloxy,naphthylidinyloxy, quinolanyloxy, quinazolinyloxy, cinnolinyloxy,pteridinyloxy, carbazolyloxy, phenanthridinyloxy, acridinyloxy,dibenzofuranyloxy, benzoimidazolyloxy, benzoisoxazolyloxy,benzooxazolyloxy, benzooxadiazolyloxy, benzoisothiazolyloxy,benzothiazolyloxy, benzofuryloxy, benzothienyloxy, dibenzothienyloxy andbenzodioxolyloxy are exemplified. Preferably furyloxy, thienyloxy,imidazolyloxy, pyrazolyloxy, isothiazolyloxy, isoxazolyloxy,oxazolyloxy, thiazolyloxy, pyridyloxy, pyrazinyloxy, pyrimidinyloxy andpyridazinyloxy are exemplified

In the present specification, a term of “heteroarylthio” includes asubstituent group in which a sulfur atom is substituted with one“heteroaryl” above. For example, pyrrolylthio, furylthio, thienylthio,imidazolylthio, pyrazolylthio, isothiazolylthio, isoxazolylthio,oxazolylthio, thiazolylthio, pyridylthio, pyrazinylthio,pyrimidinylthio, pyridazinylthio, tetrazolylthio, oxadiazolylthio,thiadiazolylthio, indolidinylthio, isoindolynylthio, indolylthio,indazolylthio, purinylthio, quinolidinylthio, isoquinolylthio,quinolylthio, phtharazinylthio, naphthylidinylthio, quinolanylthio,quinazolinylthio, cinnolinylthio, pteridinylthio, carbazolylthio,phenanthridinylthio, acridinylthio, dibenzofuranylthio,benzoimidazolylthio, benzoisoxazolylthio, benzooxazolylthio,benzooxadiazolylthio, benzoisothiazolylthio, benzothiazolylthio,benzofurylthio, benzothienylthio, dibenzothienylthio andbenzodioxolylthio etc. are exemplified. Preferably furylthio,thienylthio, imidazolylthio, pyrazolylthio, isothiazolylthio,isoxazolylthio, oxazolylthio, thiazolylthio, pyridylthio, pyrazinylthio,pyrimidinylthio, and pyridazinylthio etc. are exemplified.

In the present specification, a term of “heteroarylsulfinyl” includes asubstituent group in which sulfinyl is substituted with one “heteroaryl”above. For example, pyrrolylsulfinyl, furylsulfinyl, thienylsulfinyl,imidazolylsulfinyl, pyrazolylsulfinyl, isothiazolylsulfinyl,isoxazolylsulfinyl, oxazolylsulfinyl, thiazolylsulfinyl,pyridylsulfinyl, pyrazinylsulfinyl, pyrimidinylsulfinyl,pyridazinylsulfinyl, tetrazolylsulfinyl, oxadiazolylsulfinyl,thiadiazolylsulfinyl, indolidinylsulfinyl, isoindolynylsulfinyl,indolylsulfinyl, indazolylsulfinyl, purinylsulfinyl,quinolidinylsulfinyl, isoquinolylsulfinyl, quinolylsulfinyl,phtharazinylsulfinyl, naphthylidinylsulfinyl, quinolanylsulfinyl,quinazolinylsulfinyl, cinnolinylsulfinyl, pteridinylsulfinyl,carbazolylsulfinyl, phenanthridinylsulfinyl, acridinylsulfinyl,dibenzofuranylsulfinyl, benzoimidazolylsulfinyl,benzoisoxazolylsulfinyl, benzooxazolylsulfinyl,benzooxadiazolylsulfinyl, benzoisothiazolylsulfinyl,benzothiazolylsulfinyl, benzofurylsulfinyl, benzothienylsulfinyl,dibenzothienylsulfinyl and benzodioxolylsulfinyl etc. are exemplified.Preferably furylsulfinyl, thienylsulfinyl, imidazolylsulfinyl,pyrazolylsulfinyl, isothiazolylsulfinyl, isoxazolylsulfinyl,oxazolylsulfinyl, thiazolylsulfinyl, pyridylsulfinyl, pyrazinylsulfinyl,pyrimidinylsulfinyl and pyridazinylsulfinyl etc. are exemplified.

In the present specification, a term of “heteroarylsulfonyl” includes asubstituent group in which sulfonyl is substituted with one “heteroaryl”above. For example, pyrrolylsulfonyl, furylsulfonyl, thienylsulfonyl,imidazolylsulfonyl, pyrazolylsulfonyl, isothiazolylsulfonyl,isoxazolylsulfonyl, oxazolylsulfonyl, thiazolylsulfonyl,pyridylsulfonyl, pyrazinylsulfonyl, pyrimidinylsulfonyl,pyridazinylsulfonyl, tetrazolylsulfonyl, oxadiazolylsulfonyl,thiadiazolylsulfonyl, indolizinylsulfonyl, isoindolylsulfonyl,indolylsulfonyl, indazolylsulfonyl, purinylsulfonyl,quinolidinylsulfonyl, isoquinolylsulfonyl, quinolylsulfonyl,phtharazinylsulfonyl, naphthilidinylsulfonyl, quinolanyl sulfonyl,quinazolinylsulfonyl, cinnolinylsulfonyl, pteridinylsulfonyl,carbazolylsulfonyl, phenanthridinylsulfonyl, acridinylsulfonyl,dibenzofuranylsulfonyl, benzoimidazolylsulfonyl,benzoisoxazolylsulfonyl, benzooxazolylsulfonyl,benzooxadiazolylsulfonyl, benzoisothiazolylsulfonyl,benzothiazolylsulfonyl, benzofurylsulfonyl, benzothienylsulfonyl,dibenzothienylsulfonyl and benzodioxolylsulfonyl are exemplified.Preferably furylsulfonyl, thienylsulfonyl, imidazolylsulfonyl,pyrazolylsulfonyl, isothiazolylsulfonyl, isoxazolylsulfonyl,oxazolylsulfonyl, thiazolylsulfonyl, pyridylsulfonyl, pyrazinylsulfonyl,pyrimidinylsulfonyl and pyridazinylsulfonyl are exemplified.

In the present specification, a term of “heteroarylsulfonyloxy” includesa substituent group in which an oxygen atom is substituted with one“heteroarylsulfonyl” above. For example, pyrrolylsulfonyloxy,furylsulfonyloxy, thienylsulfonyloxy, imidazolylsulfonyloxy,pyrazolylsulfonyloxy, isothiazolylsulfonyloxy, isoxazolylsulfonyloxy,oxazolylsulfonyloxy, thiazolylsulfonyloxy, pyridylsulfonyloxy,pyrazinylsulfonyloxy, pyrimidinylsulfonyloxy, pyridazinylsulfonyloxy,tetrazolylsulfonyloxy, oxadiazolylsulfonyloxy, thiadiazolylsulfonyloxy,indolizinylsulfonyloxy, isoindolylsulfonyloxy, indolylsulfonyloxy,indazolylsulfonyloxy, purinylsulfonyloxy, quinolidinylsulfonyloxy,isoquinolylsulfonyloxy, quinolylsulfonyloxy, phtharazinylsulfonyloxy,naphthilidinylsulfonyloxy, quinolanylsulfonyloxy,quinazolinylsulfonyloxy, cinnolinylsulfonyloxy, pteridinylsulfonyloxy,carbazolylsulfonyloxy, phenanthridinylsulfonyloxy, acridinylsulfonyloxy,dibenzofuranylsulfonyloxy, benzoimidazolylsulfonyloxy,benzoisoxazolylsulfonyloxy, benzooxazolylsulfonyloxy,benzooxadiazolylsulfonyloxy, benzoisothiazolylsulfonyloxy,benzothiazolylsulfonyloxy, benzofurylsulfonyloxy,benzothienylsulfonyloxy, dibenzothienylsulfonyloxy andbenzodioxolylsulfonyloxy etc. are exemplified. Preferably,furylsulfonyloxy, thienylsulfonyloxy, imidazolylsulfonyloxy,pyrazolylsulfonyloxy, isothiazolylsulfonyloxy, isoxazolylsulfonyloxy,oxazolylsulfonyloxy, thiazolylsulfonyloxy, pyridylsulfonyloxy,pyrazinylsulfonyloxy, pyrimidinylsulfonyloxy and pyridazinylsulfonyloxyetc. are exemplified.

In the present specification, a term of “aromatic carbocyclic ring”includes an aromatic monocyclic or fused carbocyclic ring and forexample, a benzene ring, a naphthalene ring and an anthracene ring areexemplified. A benzene ring is preferred.

In the present specification, a term of “aromatic heterocyclic ring”includes an aromatic monocyclic or fused heterocyclic ring. For example,a pyrrole ring, a furan ring, a thiophen ring, a pyrazole ring, animidazole ring, an isothiazole ring, an isoxazole ring, an oxazole ring,a thiazole ring, a pyrazine ring, a pyrimidine ring, a pyridazine ring,a tetrazole ring, an oxadiazole ring, a thiadiazole ring, an indolizinering, an isoindole ring, an indole ring, an indazole ring, a purinering, a quinolidine ring, an isoquinoline ring, a quinoline ring, aphtharazine ring, a naphthyridine ring, a quinolane ring, a quinazolinering, a cinnoline ring, a pteridine ring, a carbazole ring, aphenanthridine ring, an acridine ring, a dibenzofuran ring, abenzoimidazole ring, a benzoisoxazole ring, a benzooxazole ring, abenzooxadiazole ring, a benzoisothiazole ring, a benzothiazole ring, abenzofuran ring, a benzothiophen ring, a dibenzothiophen ring and abenzodixolane ring are exemplified. Preferably a pyridine ring, a furanring and a thiophen ring are exemplified.

In the present specification, a term of “C1-C6 alkylene” includes astraight or branched alkylene group having one to six carbon atoms, andfor example, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH(CH₃)CH₂—,—C(CH₃)₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂— and—CH₂CH₂CH₂CH₂CH₂CH₂— are exemplified. Preferably, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂— and —CH₂CH₂CH₂CH₂— are exemplified.

In the present specification, a term of “alkylene optionally containingone or two heteroatom(s)” includes a straight or branched alkylene grouphaving one to six carbon atoms, optionally containing one or twoheteroatom(s) which may be substituted with “alkyl” above, and forexample, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂O—, —OCH₂CH₂—,—CH₂CH₂S—, —SCH₂CH₂—, —CH₂CH₂OCH₂CH₂—, —OCH₂CH₂O—, —OCH₂O—,—NHCH₂CH₂CH₂— and —N(CH₃)CH₂CH₂CH₂— etc. are exemplified. Preferably,—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —OCH₂CH₂O—, —OCH₂O— and—N(CH₃)CH₂CH₂CH₂— are exemplified.

In the present specification, a term of “alkenylene optionallycontaining one or two heteroatom(s)” includes a straight or branchedalkenylene group having two to six carbon atoms, optionally containingone or two heteroatom(s) which may be substituted with “alkyl” above,and for example, —CH═CHCH═CH—, —CH═CHO—, —OCH═CH—, —CH═CHS—, —SCH═CH—,—CH═CHNH—, —NHCH═CH—, —CH═CH—CH═N— and —N═CH—CH═CH— are exemplified.Preferably, —CH═CHCH═CH—, —CH═CHCH═N— and —N═CHCH═CH— are exemplified.

In the present specification, a term of “alkynylene optionallycontaining one or two heteroatom(s)” includes a straight or branchedalkynylene group having two to six carbon atoms, optionally containingone or two heteroatom(s) which may be substituted with “alkyl” above,and for example, —C≡CCH₂—, —CH₂C≡CCH₂—, —CH₂C≡CCH₂O—, —OCH₂C≡CH—,—CH₂C≡CCH₂S—, —SCH₂C≡CH—, —CH₂C≡CCH₂NH—, —NHCH₂C≡CH—, —CH₂C≡CCH₂N(CH₃)—and —N(CH₃)CH₂C≡CH— are exemplified. Especially, —CH₂C≡CCH₂— and—OCH₂C≡CH— are preferred.

In the present specification, examples of “3- to 8-memberednitrogen-containing non-aromatic heterocyclic ring” includes rings shownin the formulae of

In the present specification, a term of “3- to 8-memberednitrogen-containing heteroaromatic ring” includes a 3- to 8-memberedheteroaromatic ring containing one or more of nitrogen atom(s), andfurther optionally an oxygen atom and/or sulfur atom in the ring. Forexample, pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl(e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl,3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl), isoxazolyl (e.g.,3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g.,2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl(e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl),pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl (e.g., 1H-tetrazolyl),oxadiazolyl (e.g., 1,3,4-oxadiazolyl) and thiadiazolyl (e.g.,1,3,4-thiadiazolyl) are exemplified.

In the present specification, examples of “5- or 6-memberednitrogen-containing heteroaromatic ring containing only one nitrogenatom as a heteroatom” includes rings shown in the formulae of

In the present specification, examples of substituents in “optionallysubstituted alkyl”, “optionally substituted alkyloxy”, “optionallysubstituted alkylthio”, “optionally substituted alkylsulfinyl”,“optionally substituted alkylsulfonyl”, “optionally substitutedalkylsulfonyloxy” and “the optionally substituted alkyloxycarbonyl”include cycloalkyl, alkylene optionally containing one or twoheteroatom(s), hydroxy, oxo, alkyloxy optionally substituted with asubstituent group A at one to three position(s), mercapto, alkylthio,halogen atom, nitro, cyano, carboxy, alkyloxycarbonyl, optionallysubstituted amino, optionally substituted carbamoyl, acyl, aryloptionally substituted with a substituent group B at one to threeposition(s) (e.g., phenyl), heteroaryl optionally substituted with asubstituent group C at one to three position(s) (e.g., pyridyl, furyl,thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl), optionallysubstituted non-aromatic heteroaromatic ring group which may besubstituted with a substituent group C at one to three position(s)(e.g., morpholinyl, pyrrolidinyl, piperadinyl), aryloxy optionallysubstituted with a substituent group B at one to three position(s)(e.g., phenyloxy), alkylsulfonyl and the like. These can be substitutedwith one to three substituent(s) at any possible position.

In the present specification, examples of substituents in “optionallysubstituted alkenyl”, “optionally substituted alkynyl”, “optionallysubstituted alkenyloxy”, “optionally substituted alkynyloxy”,“optionally substituted alkenylthio”, “optionally substitutedalkynylthio”, “optionally substituted alkenyloxycarbonyl”, “optionallysubstituted alkynyloxycarbonyl”, “optionally substituted cycloalkyl”,“optionally substituted cycloalkenyl”, “optionally substitutedcycloalkyloxy, “optionally substituted cycloalkenyloxy, “optionallysubstituted cycloalkylthio”, “optionally substituted cycloalkenylthio”,“optionally substituted cycloalkylsulfinyl”, “optionally substitutedcycloalkenylsulfinyl”, “optionally substituted cycloalkylsulfonyl”,“optionally substituted cycloalkenylsulfonyl”, “optionally substitutedcycloalkylsulfonyloxy”, “optionally substitutedcycloalkenylsulfonyloxy”, “optionally substituted alkenyloxycarbonyl”,“optionally substituted C1-C6 alkylene”, “optionally substitutedalkenylene” and “the optionally substituted alkynylene” include alkyloptionally substituted with a substituent group D at one to threeposition(s), cycloalkyl, alkylene optionally containing one or twoheteroatom(s), hydroxy, oxo, alkoxyl optionally substituted with asubstituent group A at one to three position(s), mercapto, alkylthio, ahalogen atom, nitro, cyano, carboxy, alkyloxycarbonyl, optionallysubstituted amino, optionally substituted carbamoyl, acyl acyloxy, aryloptionally substituted with a substituent group B at one to threeposition(s) (e.g., phenyl), heteroaryl optionally substituted with asubstituent group C at one to three position(s) (e.g., pyridyl, furyl,thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl), non-aromaticheterocyclic group optionally substituted with a substituent group C atone to three position(s) (e.g., morpholinyl, pyrrolidinyl, piperadinyl),aryloxy optionally substituted with a substituent group C at one tothree position(s) (e.g., phenyloxy), alkylsulfonyl and the like. Thesecan be substituted with one or more substituent(s) at any possibleposition.

In the present specification, examples of substituents in “optionallysubstituted aryl”, “optionally substituted phenoxy”, “optionallysubstituted aryloxy”, “optionally substituted phenylthio”, “optionallysubstituted arylthio”, “optionally substituted arylsulfinyl”,“optionally substituted arylsulfonyl”, “optionally substitutedarylsulfonyloxy”, “optionally substituted heteroaryl”, “optionallysubstituted heteroaryloxy”, “optionally substituted heteroarylthio”,“optionally substituted heteroarylsulfinyl”, “optionally substitutedheteroarylsulfonyl”, “optionally substituted heteroarylsulfonyloxy” and“optionally substituted non-aromatic heterocyclic group” include alkyloptionally substituted with a substituent group D at one to threeposition(s), cycloalkyl, alkenyl, alkynyl, hydroxy, alkyloxy optionallysubstituted with a substituent group A at one to three position(s),aryloxy optionally substituted with a substituent group B at one tothree position(s) (e.g., phenoxy), mercapto, alkylthio, a halogen atom,nitro, cyano, carboxy, alkyloxycarbonyl, acyl, alkylsulfonyl, optionallysubstituted amino, optionally substituted carbamoyl, aryl optionallysubstituted with a substituent group B at one to three position(s)(e.g., phenyl), heteroaryl optionally substituted with a substituentgroup C at one to three position(s) (e.g., pyridyl, furyl, thienyl,imidazolyl, oxazolyl, thiazolyl, pyrazolyl), non-aromatic heterocyclicgroup optionally substituted with a substituent group C at one to threeposition(s) (e.g., morpholinyl, pyrrolidinyl, piperadinyl) and the like.These can be substituted with one or more substituent(s) at any possibleposition.

Substituent group A is a group of a halogen atom and phenyl optionallysubstituted with one to three substituent(s) selected from theSubstituent group B.

Substituent group B is a group of a halogen atom, alkyl, alkyloxy, cyanoand nitro.

Substituent group C is a group of a halogen atom and alkyl.

Substituent group D is a group of a halogen atom and alkyloxy.

In the specification a term of “carboxy equivalent” means a biologicalequivalent and includes substituents having the same polar effect as acarboxy group. For example, —CONHCN, —CONHOH, —CONHOMe, —CONHOt-Bu,—CONHOCH₂Ph, —SO₃H, —SO₂NH₂, —SO₂NHMe, —NHCONH₂, —NHCONMe₂, —P(═O)(OH)₂,—P(═O)(OH)(OEt), —P(═O)(OH)NH₂, —P(═O)(OH)NHMe, —CONHSO₂Ph, —SO₂NHCOMe,—SO₂NHCOPh, and the formula;

are exemplified.

Preferably, —CONHOt-Bu, —CONHOCH₂Ph, —SO₃H, —CONHSO₂Ph, —SO₂NHCOMe,—SO₂NHCOPh, and the formula;

are exemplified.

Groups of preferred substituents in the ring A, ring B, the formula of—X¹═X²—X³═X⁴—, R¹ to R⁹, M, Y, L¹, L², L³, n and q of the compound ofgeneral formula (I) are shown with (Ia) to (IIk). Compounds havingpossible combination of them are preferable. The substituent of thegeneral formula (I) is applicable as each corresponding substituent ofthe formula (I-a) and (I-b).

In the ring A, (Ia) a benzen ring, a furan ring, a thiophen ring or afuran ring is preferable, and further (Ib) a benzene ring or a pyridinering is preferable.

In the ring B, (Ic) a formula of

is preferable, (Id) a formula of

is more preferable, (Ie) a formula of

is further more preferable, and (If) a formula of

is most preferable.

In the formula of —X¹═X²—X³═X⁴—, (Ig) a formula of—N═C(R²)—C(R³)═C(R⁴)—, —C(R¹)═C(R²)—N═C(R⁴)— or —C(R¹)═C(R²)—C(R³)═N— ispreferable, and (Ih) a formula of —C(R¹)═C(R²)—C(R³)═N— is furtherpreferable.

In R¹, R², R⁴ and R⁵ independently, (Ii) a hydrogen atom, a halogenatom, optionally substituted alkyl, optionally substituted alkyloxy,optionally substituted amino, cyano, nitro, optionally substituted arylor optionally substituted heteroaryl is preferable, (Ij) a hydrogenatom, a halogen atom or optionally substituted alkyl is more preferableand (Ik) a hydrogen atom is most preferable.

In R³, (Il) a hydrogen atom, a halogen atom, optionally substitutedalkyl, optionally substituted alkyloxy, optionally substitutedcycloalkyloxy, optionally substituted amino, acyl, optionallysubstituted carbamoyl, cyano, nitro, optionally substituted aryl,optionally substituted heteroaryl or optionally substituted non-aromaticheterocyclic group is preferable, (Im) a hydrogen atom, a halogen atom,optionally substituted alkyl, optionally substituted alkyloxy,optionally substituted amino, optionally substituted carbamoyl,optionally substituted aryl, optionally substituted heteroaryl oroptionally substituted non-aromatic heterocyclic group is morepreferable and (In) a halogen atom, optionally substituted alkyloxy,optionally substituted amino, optionally substituted aryl, optionallysubstituted heteroaryl or optionally substituted non-aromaticheterocyclic group is most preferable.

In R⁶, (Io) optionally substituted C1-C6 alkyloxy, optionallysubstituted C1-C6 alkylthio, optionally substituted C3-C6 cycloalkyloxy,optionally substituted C3-C6 cycloalkylthio, optionally substitutedaryloxy, or optionally substituted arylthio is preferable, (Ip)optionally substituted C1-C6 alkyloxy or optionally substituted C1-C6alkylthio is further preferable, and (Iq) C2-C4 alkyloxy is mostpreferable.

In R⁷, (Ir) a halogen atom, optionally substituted alkyl, optionallysubstituted alkyloxy, cyano, nitro, optionally substituted aryl oroptionally substituted heteroaryl is preferable, (Is) a halogen atom,optionally substituted alkyl, optionally substituted aryl or optionallysubstituted heteroaryl is further preferable, and (It) a halogen atom oroptionally substituted alkyl is most preferable.

In R⁸, (Iu) optionally substituted alkyl or oxo is preferable, and (Iv)optionally substituted alkyl is further preferable.

In R⁹, (Iw) carboxy or a carboxy-equivalent is preferable, and (Ix)carboxy is further preferable.

In M, (Iy) sulfonyl is preferable, and (Iz) sulfonyl is furtherpreferable.

In Y, (IIa) a single bond or optionally substituted alkylene optionallycontaining one or two heteroatom(s) is preferable, and (IIb) a singlebond is further preferable.

In L¹, (IIc) a single bond is preferable.

In L², (IId) a single bond is preferable.

In L³, (IIe) optionally substituted alkylene optionally containing oneor two heteroatom(s) is preferable, (IIf) optionally substitutedalkylene is further preferable, and (IIg) methylene is most preferable.

In n, (IIh) 0 or 1 is preferable, and (IIi) 0 is further preferable.

In q, (IIj) 0, 1 or 2 is preferable, and (IIk) 0 or 1 is furtherpreferable.

Preferable substituent groups of the ring C, the formula of—X¹═X²—X³═X⁴—, R¹ to R⁵, R¹² to R¹⁴, Y, Z, L⁴, n and q of the generalformula (II) are shown below with (Id) above to (Iv) above, (Iy) aboveto (IIb) above, (IIh) above to (IIk) above and (IIl) to (IIm). Thecompounds with the possible combination thereof are preferable. Thesubstituent of the general formula (II) is applicable for eachcorresponding substituent of the general formula (II-a) or (II-b).

In the ring C, (Id) above is preferable, (Ie) above is furtherpreferable and (If) above is most preferable.

In the formula of —X═X²—X³═X⁴—, (Ig) above is preferable and (Ih) aboveis further preferable.

In R¹, R², R⁴ and R⁵ each substituent is independent, and (Ii) above ispreferable, (Ij) above is further preferable and (Ik) above is mostpreferable.

In R³, (Il) above is preferable, (Im) above is further preferable and(In) above is most preferable.

In R¹², (Io) above is preferable, (Ip) above is further preferable and(Iq) above is most preferable.

In R¹³, (Ir) above is preferable, (Is) above is further preferable and(It) above is most preferable.

In R¹⁴, (Iu) above is preferable and (Iv) above is further preferable.

In M, (Iy) above is preferable and (Iz) above is further preferable.

In Y, (IIa) above is preferable and (IIb) above is further preferable.

In Z, (IIl) CH, C(R¹⁴) or N is preferable and (IIm) CH is furtherpreferable.

In n, (IIh) above is preferable and (IIi) above is further preferable.

In q, (IIj) above is preferable and (IIk) above is further preferable.

Preferable substituent groups of the ring D, R¹⁵ to R²¹, M, Z, n and qof the general formula (III) are shown below with (Ie) above to (If)above, (Ii) above to (It) above, (Iy) above to (Iz) above and (IIh)above to (IIm) above. The compounds with the possible combinationthereof are preferable. The substituent of the general formula (III) isapplicable for each corresponding substituent of the general formula(III-b).

In the ring D, (Ie) above is preferable, (If) is further preferable.

In R¹⁵, R¹⁶, and R¹⁸ each substituent is independent, and (Ii) above ispreferable, (Ij) above is further preferable and (Ik) above is mostpreferable.

In R¹⁷, (Il) above is preferable, (Im) above is further preferable and(In) above is most preferable.

In R¹⁹, (Io) above is preferable, (Ip) above is further preferable and(Iq) above is most preferable.

In R²⁰, (Ir) above is preferable, (Is) above is further preferable and(It) above is most preferable.

In M, (Iy) CH, C(R¹⁴) or N is preferable and (Iz) CH is furtherpreferable.

In Z, (IIl) CH, C(R¹⁴) or N is preferable and (IIm) CH is furtherpreferable.

In n, (IIh) above is preferable and (IIi) above is further preferable.

In q, (IIj) above is preferable and (IIk) above is further preferable.

EFFECT OF INVENTION

The compounds of the present invention are useful as a therapeuticagent, especially for treating allergic diseases, since they have anexcellent DP receptor antagonistic activity and high safety.

BEST MODE FOR CARRYING OUT THE INVENTION

The compounds of the present invention can be prepared by the method A,B, C and D set forth below according to methods of Bioorg. Med. Chem.Lett., 1992, 2, 1053; Journal of Medicinal Chemistry (1963), 6(5),480-3; J. Org. Chem., 1991, 56, 4481; and Protective Groups in OrganicSynthesis, Theodora W Green (John Wiley & Sons). In addition, a racemateor an optical isomer is included in chemical structures shown by thegeneral formulae (I) to (XXII), (IV-I), (I-a), (II-a), (I-b), (II-b) and(III-b).

Method A is set forth below,

wherein the ring A and B, X¹, X², X³, X⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Y, M, L¹,L², L³, n and q are the same as 1) above; Hal is a halogen atom,alkylsulfonyloxy or arylsulfonyloxy; and Q is a protecting group.

Step 1 is a process in which the compound of the formula (IV) iscondensed with the compound of the formula (V) or (VI) to give thecompound of the formula (VII).

The reaction can be carried out in a solvent by reacting 0.5-5.0equivalents of the compound (V) or (VI) compared to the compound (IV) at25° C. to a reflux temperature of the solvent for 5 minutes to 48 hoursunder the presence of a base.

Examples of the preferable base include sodium methoxide, sodiumethoxide, potassium carbonate, sodium carbonate and the like. 0.5-5.0equivalents of the base can be used compared to the compound (IV).

Examples of the preferable solvent include methanol, ethanol,tetrahydrofuran, N,N-dimethylformamide and the like, which can be usedalone or as a mixed solvent.

If necessary, reduction can be performed by hydrogenation under thepresence of a catalyst such as 10% palladium carbon, for example.

Step 2 is a process in which the compound of the formula (VII) iscondensed with the compound of the formula (VIII), and then the productis deprotected to give the compound of the formula (IX).

The condensation reaction can be carried out in a solvent by reacting0.5-5.0 equivalents of the compound (VIII) compared to the compound(VII) at 0° C. to 100° C. for 5 minutes to 48 hours under the presenceof a base.

Examples of the preferable base include sodium hydride, potassiumhydride, potassium t-butoxide, potassium carbonate, cesium carbonate andthe like. 0.5-5.0 equivalents of the base can be used compared to thecompound (VII).

In addition, 0.1 to 1.0 equivalent of a phase transfer catalyst such astetrabutylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium iodide, benzyltriethylammonium chloride andbenzyltributylammonium chloride etc., may be used.

Examples of the preferable solvent include pyridine, acetonitrile,methylene chloride, tetrahydrofuran, N,N-dimethylformamide,dimethylsulfoxide, acetone, methylethylketone, methylisobutylketone andthe like, which can be used alone or as a mixed solvent containingwater.

In the deprotecting reaction, Q of the protecting group is removed underusual deprotecting condition.

Step 3 is a process in which the compound of the formula (IX) iscondensed with the compound of the formula (X), and then the product ishydrolyzed to give the compound of the formula (I).

The condensation reaction can be carried out in a solvent by reacting0.5-5.0 equivalents of the compound (X) compared to the compound (IX) at0° C. to 80° C. for 5 minutes to 48 hours.

The reaction may be carried out under the presence of one to fiveequivalent(s) of a base. Examples of the preferable base includetriethylamine, pyridine, potassium carbonate, sodium carbonate,potassium bicarbonate, sodium bicarbonate, potassium hydroxide, sodiumhydroxide and the like.

Examples of the preferable solvent include pyridine, acetonitrile,methylenechloride, tetrahydrofuran and the like, which can be used aloneor as a mixed solvent containing water.

The hydrolysis reaction can be carried out by using 0.5-5.0 equivalentsof the base compared to the compound (IX) in a solvent at 0° C. to 100°C. for 5 minutes to 48 hours.

Examples of the preferable base include sodium hydroxide, potassiumhydroxide, and the like.

Examples of the preferable solvent include methanol, tetrahydrofuran andthe like, which can be used alone or as a mixed solvent containingwater.

Method B is set forth below,

wherein the ring C, X¹, X², X³, X⁴, R¹², R¹³, R¹⁴, n and q are the sameas 13) above.

The compound of the formula (II) can be prepared from the compound ofthe formula (XI) in the manner similar to the steps 1-3 of the method A

Method C is set forth below,

wherein the ring C, R¹, R², R³, R⁵, R¹², R¹³, R¹⁴, Y, n and Z are thesame as 13) above; R²² is C1-C6 alkyl; and Hal is a halogen atom,alkylsulfonyloxy or arylsulfonyloxy.

The compound of the formula (XII) prepared from the compound of theformula (XI) through a process similar to the step 1 of the method A canbe used as a starting compound.

Step 1 is a process in which the compound of the formula (XII) isoxidized to give the compound of the formula (XIII).

The reaction can be carried out in a solvent by reacting 0.5-5.0equivalents of a oxidizing agent compared to the compound (XII) at −20°C. to a reflux temperature of the solvent for 5 minutes to 48 hours.

Examples of the preferable oxidizing agent include m-chloroperbenzoicacid and the like.

Examples of the preferable solvent include methylenechloride,chloroform, toluene and the like, which can be used alone or as a mixedsolvent.

Step 2 is a process in which the compound of the formula (XIII) isreacted with benzoyl bromide to give the compound of the formula (XIV).

The reaction can be carried out in a solvent by reacting 0.5-5.0equivalents of benzoyl bromide compared to the compound (XIII) at 0° C.to a reflux temperature of the solvent for 5 minutes to 48 hours.

Examples of the preferable solvent include methylene chloride,chloroform, toluene, tetrahydrofuran, N,N-dimethylformamide and thelike, which can be used alone or as a mixed solvent.

Step 3 is a process in which the compound of the formula (XIV) ishydrolyzed, and then condensed with the compound of the formula (VIII)to give the compound of the formula (XV).

The hydrolysis reaction can be carried out by using 0.5-5.0 equivalentsof the base compared to the compound (XIV) in a solvent at 0° C. to 100°C. for 5 minutes to 48 hours.

Examples of the preferable base include lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like.

Examples of the preferable solvent include methanol, tetrahydrofuran andthe like, which can be used alone or as a mixed solvent containingwater.

The condensation reaction can be carried out in a solvent by reacting0.5-5.0 equivalents of the compound (VIII) at 0° C. to 100° C. for 5minutes to 48 hours under the presence of a base.

Examples of the preferable base include sodium hydride, potassiumhydride, potassium t-butoxide, potassium carbonate, cesium carbonate andthe like. 0.5-5.0 equivalents of the base can be used compared to thecompound (VII).

In addition, 0.1 to 1.0 equivalent of a phase transfer catalyst such astetrabutylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium iodide, benzyltriethylammonium chloride andbenzyltributylammonium chloride etc., may be used.

Examples of the preferable solvent include pyridine, acetonitrile,methylene chloride, tetrahydrofuran, N,N-dimethylformamide,dimethylsulfoxide, acetone, methylethylketone, methylisobutylketone andthe like, which can be used alone or as a mixed solvent containingwater.

Step 4 is a process in which Br of the compound of the formula (XV) issubstituted with R³, and then the product is hydrolyzed to give thecompound of the formula (XVI).

In the substitution reaction in which R³ is aryl or heteroaryl, usualcondition of Suzuki coupling reaction is applicable for the reaction.

In the substitution reaction in which R³ is a electron-donating groupsuch as alkyloxy or optionally substituted amino, the substitutionreaction can be carried out in a solvent by using a metal salt ofalcohol (e.g., methanol or ethanol), optionally substituted amino or ametal salt thereof as a nucleophile at 0° C. to 200° C. for 5 minutes to48 hours.

Examples of the preferable solvent include alcohol such as methanol orethanol, N,N-dimethylformamide, dioxane, toluene and the like, which canbe used alone or as a mixed solvent containing water. If necessary, asealed tube or a microwave is applicable for the reaction.

If R³ is alkyl or alkoxycarbonyl etc., which is not available as anucleophile in the substitution reaction, Br can be substituted byreacting with alkyl halide or dialkyl oxalate after the compound (XV) islithiated by using n-BuLi for example.

The hydrolysis reaction can be carried out by using 0.5-5.0 equivalentsof the base compared to the compound (XIV) in a solvent at 0° C. to 100°C. for 5 minutes to 48 hours.

Examples of the preferable base include lithium hydroxide, sodiumhydroxide, potassium hydroxide, and the like.

Examples of the preferable solvent include methanol, tetrahydrofuran andthe like, which can be used alone or as a mixed solvent containingwater.

Method D is set forth below,

wherein the ring C, R¹, R², R³, R⁵, R¹²R¹³R¹⁴, Y, Z, L⁴, n and q are thesame as 13) above; R²² is C1-C6 alkyl; and Hal is a halogen atom,alkylsulfonyloxy or arylsulfonyloxy.

Step 1 is a process in which the compound of the formula (XIV) ishydrolyzed to give the compound of the formula (XVII).

The hydrolysis reaction can be carried out by using 0.5-5.0 equivalentsof the base compared to the compound (XIV) in a solvent at 0° C. to 100°C. for 5 minutes to 48 hours.

Examples of the preferable base include lithium hydroxide, sodiumhydroxide, potassium hydroxide, and the like.

Examples of the preferable solvent include methanol, tetrahydrofuran andthe like, which can be used alone or as a mixed solvent containingwater.

Step 2 is a process in which Br of the compound of the formula (XVII) issubstituted with R³ to give the compound of the formula (XVIII).

In the substitution reaction in which R³ is aryl or heteroaryl, usualcondition of Suzuki coupling reaction is applicable for the reaction.

In the substitution reaction in which R³ is a electron-donating groupsuch as alkyloxy or optionally substituted amino, the substitutionreaction can be carried out in a solvent by using a metal salt ofalcohol (e.g., methanol or ethanol), optionally substituted amino or ametal salt thereof as a nucleophile at 0° C. to 200° C. for 5 minutes to48 hours.

Examples of the preferable solvent include alcohol such as methanol orethanol, N,N-dimethylformamide, dioxane, toluene and the like, which canbe used alone or as a mixed solvent containing water. If necessary, asealed tube or a microwave is applicable for the reaction.

If R³ is alkyl or alkoxycarbonyl etc., which is not available as anucleophile in the substitution reaction, Br can be substituted byreacting with alkyl halide or dialkyl oxalate after the compound (XVII)is lithiated by using n-BuLi for example.

Step 3 is a process in which the compound of the formula (XVIII) iscondensed with the compound of the formula (VIII), and then hydrolyzedto give the compound of the formula (XVI).

The condensation reaction can be carried out in a solvent by reacting0.5-5.0 equivalents of the compound (VIII) compared to the compound(XVIII) at 0° C. to 100° C. for 5 minutes to 48 hours under the presenceof a base.

Examples of the preferable base include sodium hydride, potassiumhydride, potassium t-butoxide, potassium carbonate, cesium carbonate andthe like. 0.5-5.0 equivalents of the base can be used compared to thecompound (XVIII).

In addition, 0.1 to 1.0 equivalent of a phase transfer catalyst such astetrabutylammonium chloride, tetrabutylammonium bromide,tetrabutylammonium iodide, benzyltriethylammonium chloride andbenzyltributylammonium chloride etc., may be used.

Examples of the preferable solvent include pyridine, acetonitrile,methylene chloride, tetrahydrofuran, N,N-dimethylformamide,dimethylsulfoxide, acetone, methylethylketone, methylisobutylketone andthe like, which can be used alone or as a mixed solvent containingwater.

The hydrolysis reaction can be carried out by using 0.5-5.0 equivalentsof the base compared to the compound (XVIII) in a solvent at 0° C. to100° C. for 5 minutes to 48 hours.

Examples of the preferable base include lithium hydroxide, sodiumhydroxide, potassium hydroxide, and the like.

Examples of the preferable solvent include methanol, tetrahydrofuran andthe like, which can be used alone or as a mixed solvent containingwater.

6-Substituted-7-azaindole is a known compound or available as set forthbelow,

wherein R³⁷ is optionally substituted alkyl, optionally substitutedalkyloxy, optionally substituted amino, acyl, optionally substitutedcarbamoyl, cyano, nitro, optionally substituted aryl, optionallysubstituted heteroaryl or optionally substituted non-aromaticheterocyclic group; R³⁸ is optionally substituted alkyl; and Q¹ is acyl.

The compound of the formula (XIX) can be prepared by substituting Br of6-bromo-7-azaindole with R³⁷.

In the substitution reaction in which R³⁷ is aryl or heteroaryl, usualcondition of Suzuki coupling reaction is applicable for the reaction.

In the substitution reaction in which R³⁷ is a electron-donating groupsuch as alkyloxy or optionally substituted amino, the substitutionreaction can be carried out in a solvent by using a metal salt ofalcohol (e.g., methanol or ethanol), optionally substituted amino or ametal salt thereof as a nucleophile at 0° C. to 200° C. for 5 minutes to48 hours.

Examples of the preferable solvent include alcohol such as methanol orethanol, N,N-dimethylformamide, dioxane, toluene and the like, which canbe used alone or as a mixed solvent containing water. If necessary, acatalysis (e.g., palladium catalysis, cupper catalysis etc.) and/or abase may be added and a sealed tube or a microwave may be used for thereaction.

If R³⁷ is alkyl or alkoxycarbonyl etc., which is not available as anucleophile in the substitution reaction, Br can be substituted byreacting with alkyl halide or dialkyl oxalate after 6-bromo-7-azaindoleis lithiated by using n-BuLi for example.

Step 1 is a process in which the compound of the formula (XX) isprepared by a rearrangement reaction of 7-azaindole-7-oxide.

The rearrangement reaction can be carried out in a solvent at 0° C. to250° C. for 5 minutes to 48 hours.

Examples of the preferable solvent include acetic anhydride, propionicanhydride, benzoic anhydride and the like.

If necessary, the acylated hydroxy group may be deacylated usingtrifluoroacetic acid.

Step 2 is a process in which the compound of the formula (XXI) isprepared by alkylation reaction of the compound of the formula (XX).

The alkylation reaction can be carried out in a solvent at 0° C. to 250°C. for 5 minutes to 48 hours under the presence of a base.

Examples of the preferable solvent include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran and the like.

Examples of the preferable base include cesium carbonate, sodiumcarbonate, potassium carbonate, sodium hydroxide and the like, and oneto three equivalent(s) compared to the compound of the formula (XX) canbe used.

Examples of the preferable alkylation agent include methyl bromide,methyl iodide, methyl tosylate, methyl mesylate, methyl triflate,dimethyl sulfate, ethyl iodide, 1-iodopropane, 2-iodopropane,1-iodobutane, 2-iodobutane, 2-methyl-1-iodopropane, benzyl bromide,2-methyloxy-1-bromoethane and the like, and 0.8-2 equivalents of theagent compared to the compound (XX) can be used.

Step 3 is a process in which the compound of the formula (XXII) isprepared by deacylation reaction of the compound of the formula (XXI).

The deacylation reaction can be carried out in a solvent at 0° C. to250° C. for 5 minutes to 48 hours under the presence of a base.

Examples of the preferable solvent include methanol, ethanol,tetrahydrofuran and the like, which can be used alone or as a mixedsolvent containing water.

Examples of the preferable base include lithium hydroxide, sodiumhydroxide, potassium hydroxide and the like, and one to threeequivalent(s) of the base compared to the compound of the formula (XX)can be used.

In this specification, a term of “solvate” includes, for example, asolvate with an organic solvent, a hydrate and the like. In a case offorming the solvate with an organic solvent, any number of molecules ofthe organic solvent may coordinated. In a case of forming the hydrate,any number of water molecules may be coordinated. A hydrate is usuallypreferred.

A term of “compound of the present invention” includes apharmaceutically acceptable salt and a solvate thereof. Examples of thesalt include salts with alkaline metal (lithium, sodium and potassiumetc.), alkaline earth metal (magnesium and calcium etc.), ammonium,organic bases and amino acids and salts with inorganic acids(hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid,etc.) and organic acids (acetic acid, citric acid, maleic acid, fumaricacid, benzenesulfonic acid and p-toluenesulfonic acid etc.). These saltscan be formed by the usual method

A compound of the present invention is not limited to the specifiedisomer but includes all possible isomers and racemates.

A compound of the present invention shows an excellent DP receptorantagonistic activity as described in the following examples.Accordingly, a pharmaceutical composition of the present invention canbe used as a therapeutic agent for preventing and/or treating allergicdiseases such as asthma, allergic rhinitis, allergic dermatitis,allergic conjunctivitis, food allergy and the like; systemicmastocytosis; systemic disorder of mastcell-activation; lung emphysema;chronic bronchitis; chronic obstructive lung disease; skin disordercharacterized by pruritus such as atopic dermatitis and hives; diseasesoccurring secondarily due to behavior accompanied by pruritus such ascataract and retinal detachment; brain damages such as cerebrovasculardisorder, degenerative brain disorder and demyelinating disease;sleep-waking disorder; Churg-Strauss syndrome; papular dermatitis suchas filariasis; vasculitis; polyarteritis; cutaneous eosoiophilicgranuloma; autoimmune diseases such as multiple sclerosis and transplantrejection; eosoiophilic pneumonopathy; histiocytosis; pneumonia;aspergillosis; pleurisy; sarcoidosis; pulmonary fibrosis; eosinophilia;skin flush such as face flush by nicotinic acid; filariasis;schistosomiasis; trichinelliasis; coccidioidomycosis; tuberculosis;bronchial cancer; lymphoma; Hodgkin's disease and the like.

When a compound of the present invention is administered to a human inorder to treat the diseases above, oral administration through a powder,granule, tablet, capsule, pill, liquid formulation and the like, orparenteral administration through an injection, suppository, transdermalformulation, inhalant and the like is possible.

A pharmaceutical composition can be obtained by mixing a therapeuticallyeffective amount of a compound of the present invention with apharmaceutical additives such as an excipient, binder, wetting agent,disintegrating agent, lubricant and the like, which is suitable to theselected formulation. An injection can be formulated by sterilizationtogether with a suitable carrier.

In the treatment of the diseases related to PGD2 receptor above, it ispossible to use the compound of the present invention combined with orin a coupled formulation with the other therapeutic agent. In the caseof treating inflammatory diseases including allergy, the compound can beused combined with or in a coupled formulation with leukotriene receptorantagonist (e.g., montelukast sodium, zafirlukast, pranlukast hydrate,leukotriene B4 receptor antagonist); leukotriene synthesis inhibitorsuch as zileuton, PDE IV inhibitor (e.g., theophylline, cilomilast,roflumilast), corticosteroid (e.g., prednisolone, fluticasone,budesonide, ciclesonide), β2-agonist (e.g., salbutamol, salmeterol,formoterol), anti IgE antibody (e.g., omalizumab), histamine H1 receptorantagonist (e.g., chlorpheniramine, loratadine, cetirizine),immunosuppressant (tacrolimus, cyclosporin), thromboxane A2 receptorantagonist (e.g., ramatroban), chemokine receptor (especially CCR-1,CCR-2, CCR-3) antagonist, other prostanoid receptor antagonist (e.g.,CRTH2 antagonist), adhesive molecule (e.g., VLA-4 antagonist), cytokineantagonist (e.g., anti-IL-4 antibody, anti-IL-3 antibody), Non-steroidalanti-inflammatory agent (e.g., propionic acid derivative such asibuprofen, ketoprofen, and naproxen etc.; acetic acid derivative such asindomethacin, and diclofenac etc.; salicylic acid such as acetylsalicylic acid; cyclooxigenase-2 inhibitor such as celecoxib andetoricoxib).

Further, uses combined with or in a coupled formulation with antitussiveagent (e.g., codein, hydrocodein), cholesterol lowering agent(lovastatin, simvastatin, fluvastatin, rosuvastatin), anticholinergicdrug (e.g., tiotropium, ipratropium, flutropium, oxitropium) are alsopossible.

Dose of the compounds of the present invention depends on condition ofdiseases, route of administration, age and body weight of a patient. Inthe case of oral administration to an adult, the dose range is usually0.1 to 100 mg/kg/day, preferably 1 to 20 mg/kg/day.

EXAMPLES

The present invention is illustrated more in detail below by examplesand test examples, but not limited to these examples.

In examples, the following abbreviations are used;

Me: methyl Et: ethyl n-Pr: n-propyl i-Pr: isopropyl n-Bu: n-butyl i-Bu:i-butyl s-Bu: sec-butyl Ph: phenyl Ac: acetyl Boc: t-butoxycarbonyl SEM:2-(trimethylsilyl)ethoxymethyl DMF: N,N-dimethylformamide THF:tetrahydrofuran

Example 1 Preparation of the Compound E4

Step 1

A solution of 7-azaindole-7-oxide (1.00 g, 7.45 mmol) in aceticanhydride (20 ml) was heated under reflux for 4 hours and aceticanhydride was evaporated in vacuo. The resulting residue was purifiedwith a silica gel column chromatography. The obtained crystalline waswashed with isopropyl ether to give the compound E1 (609 mg, 37% yield).

¹H-NMR (CDCl₃) δ ppm: 2.38 (3H, s), 3.00 (3H, s), 6.62 (1H, d, J=4.1Hz), 6.96 (1H, d, J=8.2 Hz), 7.96 (1H, d, J=8.2 Hz), 7.97 (1H, d, J=4.1Hz).

Step 2

To a solution of the compound E1 (437 mg, 2.00 mmol) in methylenechloride (5 mL) under ice-cooling was added trifluoroacetic acid (3 mL)and the mixture was stirred at room temperature for 1 hour.Trifluoroacetic acid (2 mL) was further added and the mixture wasstirred at room temperature for additional 1 hour. pH of the solutionwas adjusted to 9 by adding an aqueous solution of sodium bicarbonateand the mixture was extracted with ethyl acetate. The organic layer waswashed with an aqueous solution of sodium bicarbonate, dried over sodiumsulfate and concentrated in vacuo. The resulting residue was purifiedwith a silica gel column chromatography to give the compound E2 (156 mg,44% yield) and the unreacted compound E1 (164 mg, 38%).

¹H-NMR (CDCl₃) δ ppm: 2.69 (3H, s), 6.47 (1H, d, J=3.8 Hz), 6.53 (1H, d,J=9.2 Hz), 7.12 (1H, br s), 7.67 (1H, d, J=9.2 Hz).

Step 3

To a solution of the compound E2 (281 mg, 1.6 mmol) in DMF (3 mL) wereadded ethyl iodide (300 mg, 1.6 mmol) and cesium carbonate (780 mg, 1.92mmol) and the mixture was stirred at room temperature for 30 minutes. pHof the reaction solution was adjusted to 4 by adding a 1M aqueoussolution of citric acid (4 mL, 4 mmol). Water (30 mL) was added to thereaction solution and the precipitated crystalline was filtered, washedwith water and dried to give the compound E3 (277 mg, 91% yield).

¹H-NMR (CDCl₃) δ ppm: 1.44 (3H, t, J=7.2 Hz), 3.00 (3H, s), 4.39 (2H, q,J=7.2 Hz), 6.51 (1H, d, J=4.2 Hz), 6.67 (1H, d, J=8.4 Hz), 7.75 (1H, d,J=8.4 Hz), 7.77 (1H, d, J=3.9 Hz).

Step 4

To a solution of the compound E3 (190 mg, 1 mmol) in MeOH (2 mL) and THF(2 mL), a 1M aqueous solution of LiOH (1.5 mL, 1.5 mmol) and the mixturewas stirred at room temperature for 15 minutes. pH of the solution wasadjusted to 4 by adding a 1M aqueous solution of citric acid (2 mL). Thereaction solution was concentrated in vacuo and water (20 mL) was addedto the residue. The precipitated crystalline was filtered, washed withwater and dried to give the compound E4 (146 mg, 87% yield).

¹H-NMR (CDCl₃) δ ppm: 1.44 (3H, t, J=7.2 Hz), 4.38 (2H, q, J=7.2 Hz),6.41-6.43 (1H, m), 6.58 (1H, d, J=8.7 Hz), 7.06-7.08 (1H, m), 7.82 (1H,d, J=8.4 Hz), 8.95 (1H, br).

The following compound E5-E12 can be prepared in the same mannerdescribed above.

TABLE 1 No. compound Structure E5 

E6 

E7 

E8 

E9 

E10

E11

E12

Example 2 Preparation of the Compound I-4

Step 1

To a solution of the compound (1) (2.0 g, 16.9 mmol) in methanol (20mL), were added 1-(t-butoxycarbonyl)-4-piperidone (6.73 g, 33.8 mmol)and a 28% methanol solution of sodium methoxide (20 mL, 0.1 mmol) andthe solution was heated under reflux for 7 hours. The reaction mixturewas poured into 100 mL of ice-water, extracted with ethyl acetate andthe organic layer was washed with water, dried and concentrated. Theresulting residue was crystallized from hexane-ethyl acetate to give thecompound (2) (2.47 g, 49% yield).

¹H-NMR (CDCl₃) δ ppm: 1.51 (s, 9H), 2.58 (m, 2H), 3.69 (t, 2H, J=5.7Hz), 4.15 (d, 2H, J=2.7 Hz), 6.16 (s, 1H), 7.42 (s, 1H), 7.79 (d, 1H,J=5.7 Hz), 8.27 (d, 1H, J=5.7 Hz), 8.86 (s, 1H).

Step 2

The compound (2) (1.05 g, 3.5 mmol) was dissolved in methanol (20 mL)and acetic acid (1 mL), and stirred under hydrogen atmosphere in thepresence of 10% palladium carbon for 3 hours. The reaction mixture wasfiltered through Celite and the filtrate was condensed. The obtainedcrystalline was filtered and dried to give the compound (3) (1.18 g, 93%yield).

¹H-NMR (CDCl₃) δ ppm: 1.49 (s, 9H), 1.61-2.02 (m, 4H), 2.16 (s, 3H),2.85-3.04 (m, 3H), 4.26 (m, 2H), 7.49 (s, 1H), 7.69 (d, 1H, J=5.7 Hz),8.08 (d, 1H, J=5.7 Hz), 9.20 (s, 1H).

Step 3

5N Hydrochloric acid (3.2 mL) was added to a solution of the compound(3) (1.16 g, 3.22 mmol) and the mixture was stirred for an hour. A 2Naqueous solution of sodium hydroxide (10 mL) was added to the reactionmixture under ice cooling and the oily product was obtained. Ethylacetate was added to the oily product and the resulting crystalline wasfiltered and dried to give the compound (4) (0.7 g, 80% yield).

¹H-NMR (DMSO-d₆) δ ppm: 1.53-1.88 (m, 4H), 2.61-3.11 (m, 5H), 7.32 (s,1H), 7.53 (d, 1H, J=5.4 Hz), 8.02 (d, 1H, J=5.4 Hz), 8.68 (s, 1H), 11.54(brs, 1H).

Step 4

To a solution of the compound (4) (564 mg, 2.0 mmol) in pyridin e (3mL), was added 4-isopropoxybenzenesulfonyl chloride (326 mg, 1.39 mmol)and the mixture was stirred at room temperature for 1.5 hours. Thereaction mixture was diluted with water, extracted with ethyl acetateand the organic layer was washed with diluted hydrochloric acid andwater successively, dried and concentrated. The resulting crystallinewas filtered and dried to give the compound (5) (256 mg, 32% yields).

¹H-NMR (CDCl₃) δ ppm: 1.39 (d, 6H, J=6.3 Hz), 1.81-1.96 (m, 2H), 2.08(brd, 2H), 2.48 (brt, 2H), 2.78 (m, 1H), 3.92 (brd, 2H), 4.65 (m, 1H),6.97 (d, 2H, J=8.7 Hz), 7.24 (s, 1H), 7.48 (d, 1H, J=5.4 Hz), 7.77 (d,2H, J=8.7 Hz), 8.17 (d, 1H, J=5.7 Hz), 8.87 (s, 1H).

Step 5

To a solution of the compound (5) (251 mg, 0.62 mmol) inN,N-dimethylformamide (3 mL), were added cesium carbonate (0.41 g, 1.26mmol) and methyl bromoacetate (119 μL, 1.26 mmol) and the mixture wasstirred for an hour. The reaction solution was diluted with water,extracted with ethyl acetate and the extract was washed with water,dried and concentrated. The resulting residue was purified with a silicagel column chromatography (hexane:ethyl acetate=2:1). The product wasdissolved in methanol (1.0 mL) and tetrahydrofuran (0.5 mL). A 1Maqueous solution of sodium hydroxide (0.49 mL, 0.49 mmol) was added tothe solution and stirred at room temperature for 2 hours. The reactionsolution was diluted with water and acidified by adding dilutedhydrochloric acid. The product was extracted with ethyl acetate and theextract was washed with water, dried and concentrated. The residue wascrystallized from hexane-ethyl acetate to give the compound I-4 (57 mg,21% yield).

mp. 262-266° C.,

¹H-NMR (DMSO-d₆) δ ppm: 1.32 (d, 6H, J=6.0 Hz), 1.58-1.74 (m, 2H), 2.00(brd, 2H), 2.37 (brt, 2H), 2.78 (m, 1H), 3.76 (brd, 2H), 4.76 (m, 1H),5.06 (s, 2H), 7.15 (d, 2H, J=8.7 Hz), 7.35 (s, 1H), 7.51 (d, 1H, J=5.7Hz), 7.68 (d, 2H, J=8.7 Hz), 8.07 (d, 1H, J=5.7 Hz), 8.72 (s, 1H).

Example 3 Preparation of the Compound I-13

Step 1

To a solution of the compound (6) (5.0 g, 42.3 mmol) in methanol (50 mL)were added 1-(t-butoxycarbonyl)-4-piperidone (16.9 g, 84.6 mmol) and a28% methanol solution of sodium methoxide (50 mL, 0.25 mmol) and thesolution was heated under reflux for 2.5 hours. The reaction solutionwas poured into 100 mL of ice water, extracted with ethyl acetate andthe organic layer was washed with water, dried and concentrated. Theresulting residue was crystallized from hexane-ethyl acetate to give thecompound (7) (9.23 g, 73% yield).

¹H-NMR (CDCl₃) δ ppm: 1.51 (s, 9H), 2.57 (s, 2H), 3.61-3.71 (m, 2H),4.14-4.24 (m, 2H), 6.15 (s, 1H), 7.13-7.18 (m, 1H), 7.40 (s, 1H), 8.22(d, 1H, J=9.3 Hz), 8.32-8.34 (m, 1H), 10.2 (br, 1H).

Step 2

The compound (7) (10.5 g, 35.1 mmol) was added to a solution of 60%sodium hydride (1.7 g, 42.5 mmol) in N,N-dimethylformamide (60 mL) at 0°C. and stirred under nitrogen atmosphere for 0.5 hours. To the reactionsolution was added 2-(trimethylsilyl)ethoxymethyl chloride (6.43 g, 38.5mmol) at −10° C. and the mixture was stirred at room temperature for 45minutes. The reaction mixture was poured into 100 mL of water, extractedwith ethyl acetate and the organic layer was washed with water, driedand concentrated to give the compound (8) (15.05 g, 99.9% yield).

¹H-NMR (CDCl₃) δ ppm: 0.96-1.01 (m, 2H), 1.57 (s, 9H), 2.62 (br, 2H),3.58-3.63 (m, 2H), 3.75 (t, 2H, J=6 Hz), 5.74 (s, 2H), 6.20 (br, 2H),7.17-7.22 (m, 1H), 1.38 (s, 1H), 8.22 (d, 1H, J=8.1 Hz), 8.40 (d, 1H,J=4.8 Hz).

Step 3

The compound (8) (20.08 g, 46.8 mmol) was dissolved in methanol (250 mL)and stirred under hydrogen atmosphere in the presence of 10% palladiumcarbon (2.5 g) for 18 hours. The reaction mixture was filtered throughCelite and the filtrate was concentrated to give the compound (9) (20.18g, 99.9% yield).

¹H-NMR (CDCl₃) δ ppm: 0.95-1.00 (m, 2H), 1.56 (s, 9H), 1.65-1.80 (m,4H), 2.07-2.12 (m, 2H), 3.61 (t, 2H, J=8.4 Hz), 4.35-4.80 (br, 2H), 5.71(s, 2H), 7.12-7.17 (m, 3H), 7.98 (d, 1H, J=7.8 Hz), 8.38 (d, 1H, J=4.5Hz).

Step 4

100 mL of 4N hydrochloric acid/1,4-dioxane was added to the compound (9)(37.47 g, 86.9 mmol) and stirred at room temperature for 18 hours. Afterthe reaction solution was condensed, ethyl acetate and a saturatedaqueous solution of sodium bicarbonate were added and the mixture wasextracted. The organic layer was washed with water, dried andconcentrated. The oily product was crystallized by adding diethyletherand filtered, dried to give the compound (10) (15 g, 50% yield).

¹H-NMR (CDCl₃) δ ppm: 0.97 (t, 2H, J=7.2 Hz), 3.18-3.21 (m, 2H),3.59-3.66 (m, 4H), 5.76 (s, 2H), 7.28-7.31 (m, 2H), 8.28 (d, 1H, J=7.8Hz), 8.40 (d, 1H, J=7.5 Hz).

Step 5

4-Propoxybenzenesulfonyl chloride (2.46 g, 10.5 mmol) was added to asolution of the compound (10) (3.45 g, 10.0 mmol) and triethylamine(2.02 g, 20.0 mmol) in N,N-dimethylformamide (20 mL) and stirred at roomtemperature for 0.5 hours. Ethyl acetate and a saturated sodiumbicarbonate aqueous solution were added to the reaction solution and themixture was extracted. The organic layer was washed with brine, driedand concentrated. The resulting residue was purified by a silica gelcolumn chromatography (hexane:ethyl acetate=2:1) and the crystallineobtained after concentration was filtered and dried to give the compound(11) (3.2 g, 59% yield).

¹H-NMR (CDCl₃) δ ppm: 0.97 (t, 2H, J=8.4 Hz), 1.47 (d, 6H, J=6 Hz),1.90-2.05 (m, 2H), 2.12-2.15 (m, 2H), 2.47-2.53 (m, 2H), 4.70-4.76 (m,1H), 5.70 (s, 2H), 7.05-7.16 (m, 4H), 7.79-7.82 (m, 2H), 7.88 (d, 1H,J=7.8 Hz), 8.38 (d, 1H, J=4.8 Hz).

Step 6

A 1M solution of tetra-n-butylammonium fluoride (270 mL) was added to asolution of the compound (11) (20.0 g, 36.8 mmol) in tetrahydrofuran(200 mL) and heated with stirring for 8 hours. The reaction solution wasconcentrated, ethyl acetate and a saturated ammonium chloride aqueoussolution was added and the mixture was extracted. The organic layer waswashed with brine, dried and concentrated. Ethyl acetate was added tothe oily residue and the obtained crystalline was filtered, dried togive the compound (12) (11.9 g, 81% yield).

¹H-NMR (CDCl₃) δ ppm: 1.31 (d, 6H, J=5.7 Hz), 1.65-1.75 (m, 2H),1.98-2.01 (m, 2H), 2.33-2.38 (m, 2H), 2.65-2.70 (m, 1H), 3.72 (d, 2H,J=11.4 Hz), 4.73-4.78 (m, 1H), 6.65-6.99 (m, 1H), 7.14-7.21 (m, 3H),7.67-7.70 (m, 2H), 7.90 (d, 1H, J=8.1 Hz), 8.16 (d, 1H, J=1.8 Hz), 11.34(s, 1H).

Step 7

m-Chloroperbenzoic acid (0.43 g, 2.51 mmol) was added to a solution ofthe compound (12) (665 mg, 1.67 mmol) in dichloromethane (30 mL) at −5°C. and stirring was continued for an hour. A saturated sodiumbicarbonate aqueous solution was added to the reaction mixture andextracted with chloroform. The organic layer was washed with water,dried and concentrated. The resulting residue was purified by a silicagel column chromatography (ethyl acetate:methanol=9:1) and theconcentrated residue was crystallized by adding ethyl acetate to givethe compound (13) (520 mg, 74% yield).

¹H-NMR (CDCl₃) δ ppm: 1.38 (d, 6H, J=6.3 Hz), 1.83-2.05 (m, 6H),2.38-2.46 (m, 2H), 2.62-2.72 (m, 1H), 3.80 (d, 2H, J=12.3 Hz), 4.60-4.67(m, 1H), 6.96-7.05 (m, 3H), 7.26 (s, 1H), 7.60 (d, 1H, J=9.9 Hz),7.69-7.72 (m, 2H), 8.18 (d, 1H, J=6.3 Hz), 12.40 (br, 1H).

Step 8

Benzoyl bromide (8.5 g, 44.55 mmol) was added to a solution of thecompound (13) (6.2 g, 14.85 mmol) in N,N-dimethylformamide (50 mL) andstirred at 80° C. for 45 minutes. A saturated sodium bicarbonate aqueoussolution was added to the reaction mixture and extracted with ethylacetate. The organic layer was washed with brine and water successively,dried and concentrated. The resulting residue was purified by a silicagel column chromatography (hexane:ethyl acetate=2:1) and the crystallineobtained after concentration was filtered and dried to give the compound(14) (3.0 g, 34% yield).

¹H-NMR (CDCl₃) δ ppm: 1.38 (d, 6H, J=6 Hz), 1.80-2.00 (m, 2H), 2.10-2.15(m, 2H), 2.40-2.50 (m, 2H), 2.70-2.78 (m, 1H), 3.90-4.00 (m, 2H),4.60-4.70 (m, 1H), 6.96-7.06 (m, 2H), 7.30-7.35 (m, 1H), 7.40-7.60 (m,3H), 7.65-7.80 (m, 5H).

Step 9

A 1M aqueous solution of sodium hydroxide (15.45 mL, 15.45 mmol) wasadded to a solution of the compound (14) (3.0 g, 5.15 mmol) in a mixedsolvent of tetrahydrofuran (60 mL) and methanol (20 mL) and stirred atroom temperature for 15 minutes. After being concentrated, a citric acidaqueous solution and ethyl acetate were added and the mixture wasextracted. The organic layer was washed with a saturated sodiumbicarbonate aqueous solution, dried and concentrated. The residue wascrystallized from ethyl acetate to give the compound (19) (2.5 g, 99.9%yield).

¹H-NMR (CDCl₃) δ ppm: 1.09 (d, 6H, J=6 Hz), 1.43-1.54 (m, 2H), 1.72-1.77(m, 2H), 2.09-2.18 (m, 2H), 2.50-2.55 (m, 1H), 3.50 (d, 2H, J=12 Hz),4.50-4.56 (m, 1H), 6.91-6.94 (m, 3H), 7.03 (s, 1H), 7.45 (d, 2H, J=8.7Hz), 7.67 (d, 1H, J=7.2 Hz), 11.41 (br, 1H).

Step 10

Methyl bromoacetate (96 mg, 0.84 mmol) and cesium carbonate (136 mg,0.42 mmol) were added to a solution of the compound (15) (200 mg, 0.42mmol) in N,N-dimethylformamide (10 mL) and stirred at room temperaturefor 18 hours. Water (200 mL) was added to the reaction solution and themixture was extracted with ethyl acetate (20 mL). The organic layer waswashed with brine, dried and concentrated. The crystalline obtainedafter concentration was filtered and dried to give the compound (16)(190 mg, 82% yield).

¹H-NMR (CDCl₃) δ ppm: 1.39 (d, 6H, J=6 Hz), 1.83-1.92 (m, 2H), 2.36-2.42(m, 2H), 2.65-2.75 (m, 2H), 3.77 (s, 3H), 3.81 (d, 2H, J=11.7 Hz),4.60-4.70 (m, 1H), 5.00 (s, 2H), 6.92 (s, 1H), 6.96-7.00 (m, 2H), 7.18(d, 1H, J=8.1 Hz), 7.67 (d, 1H, J=8.4 Hz), 7.69-7.73 (m, 2H).

Step 11

A 2M aqueous solution of lithium hydroxide (0.4 mL, 0.8 mmol) was addedto a solution of the compound (16) (70 mg, 0.127 mmol) in methanol (1.0mL) and tetrahydrofuran (4.0 mL) and stirred at room temperature for 35minutes. The reaction solution was diluted with water, acidified byadding diluted hydrochloric acid and extracted with ethyl acetate. Theextract was washed with water, dried and concentrated. The residue wascrystallized from ethyl acetate to give the compound I-13 (154 mg, 79%yield).

¹H-NMR (CDCl₃) δ ppm: 1.31 (d, 6H, J=6 Hz), 1.80-1.90 (m, 2H), 1.99-2.31(m, 2H), 2.35 (t, 2H, J=11.1 Hz), 2.70-2.80 (m, 1H), 3.73 (d, 2H, J=12Hz), 4.70-4.80 (m, 1H), 4.89 (s, 2H), 7.14 (d, 2H, J=8.7 Hz), 7.21 (d,1H, J=8.1 Hz), 7.30 (s, 1H), 7.67 (d, 2H, J=9 Hz), 7.94 (d, 1H, J=8.1Hz).

The compounds (F-1) to (F-) in the Tables 2-5 can be synthesized in thesame manner as Example 2 and 3.

TABLE 2 Compound No. Structure F1

F2

F3

F4

F5

F6

F7

F8

F9

 F10

TABLE 3 Compound No. Structure F11

F12

F13

F14

F15

F16

F17

F18

F19

F20

F21

F22

TABLE 4 Compound No. Structure F23

F24

F25

F26

F27

F28

F29

F30

F31

F32

F33

F34

TABLE 5 Compound No. Structure F35

F36

F37

F38

F39

F40

Example 4 Preparation of the Compound I-14

Step 1

To the compound (15) (60 mg, 0.125 mmol) and a 28% methanol solution ofsodium methoxide (3 mL) was added cuprous bromide (6 mg, 0.04 mmol) andthe mixture was heated with stirring at 140° C. with microwave for 10minutes. The reaction solution was added to an aqueous solution ofcitric acid (citric acid 4 g, water 25 mL) and the solution wasneutralized with sodium bicarbonate. The product was extracted withethyl acetate (30 mL) and the organic layer was washed with brine, driedand condensed. The resulting residue was crystallized from chloroformand dried to give the compound (17) (31 mg, 57% yield).

¹H-NMR (CDCl₃) δ ppm: 1.31 (d, 6H, J=6 Hz), 1.65-1.70 (m, 2H), 1.94-1.99(m, 2H), 2.30-2.40 (m, 2H), 2.65-2.75 (m, 1H), 3.70 (d, 2H, J=11.7 Hz),4.73-4.79 (m, 1H), 6.43 (d, 1H, J=8.7 Hz), 6.92 (s, 1H), 7.12-7.18 (m,2H), 7.65-7.70 (m, 2H), 7.79 (d, 1H, J=8.4 Hz), 11.17 (s, 1H).

Step 2

To a solution of the compound (17) (150 mg, 0.35 mmol) inN,N-dimethylformamide (3 mL) were added methyl bromoacetate (97 mg, 0.63mmol) and cesium carbonate (228 mg, 0.70 mmol) and the mixture wasstirred at room temperature for an hour. Water (200 mL) was added to thereaction solution, extracted with ethyl acetate (20 mL) and the organiclayer was washed with brine, dried and condensed. The resulting residuewas purified by silica gel column chromatography (chloroform:EtOH 9:1)and the crystalline obtained after condensation was filtered and driedto give the compound (8) (115 mg, 65% yield).

¹H-NMR (CDCl₃) δ ppm: 1.38 (d, 6H, J=6 Hz), 1.80-1.95 (m, 2H), 2.03-2.07(br, 2H), 2.36-2.46 (m, 2H), 2.60-2.70 (m, 1H), 3.76 (s, 3H), 3.93 (s,3H), 4.62-4.67 (m, 1H), 4.94 (s, 1H), 6.51 (d, 1H, J=8.7 Hz), 6.73 (s,1H), 6.96-6.99 (m, 2H), 7.67-7.74 (m, 3H).

Step 3

A 2M aqueous solution of lithium hydroxide (0.48 mL, 0.96 mmol) wasadded to a solution of the compound (18) (161 mg, 0.32 mmol) in methanol(3.0 mL) and tetrahydrofuran (5.0 mL) and the mixture was stirred atroom temperature for 20 minutes. The reaction solution was diluted withwater and acidified by adding diluted Hydrochloric acid and then theproduct was extracted with ethyl acetate, and the extract was washedwith water, dried and condensed. The residue was crystallized from ethylacetate to give the compound I-14 (136 mg, 87% yield).

¹H-NMR (CDCl₃) δ ppm: 1.31 (d, 6H, J=6 Hz), 1.55-1.70 (m, 2H), 1.97-2.01(m, 2H), 2.36 (t, 2H, J=11.4 Hz), 2.65-2.75 (m, 1H), 3.72 (d, 2H, J=11.4Hz), 3.83 (s, 3H), 4.73-4.80 (m, 1H), 4.85 (s, 2H), 6.47 (d, 1H, J=8.4Hz), 7.14 (s, 1H), 7.15 (d, 2H, J=8.7 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.84(d, 1H, J=9.6 Hz).

Example 5 Preparation of the Compound I-26

Step 1

A 2M aqueous solution of potassium carbonate (0.2 mL) was added to asolution of the compound (16) (55 mg, 0.100 mmol), 2-furanboronic acid(2.2 mg, 0.01 mmol), palladium acetate (2.2 mg, 0.01 mmol) andtriphenylphosphine (5.2 mg, 0.02 mmol) in N,N-dimethylformamide (1.0 mL)and the mixture was stirred under nitrogen atmosphere for 2.5 hours.Water was added to the reaction solution and extracted with ethylacetate. The organic layer was washed with brine and water successively,dried and condensed. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=1:2) and the crystallineobtained after condensation was filtered and dried to give the compound(19) (32 mg, 77% yield).

¹H-NMR (CDCl₃) δ ppm: 1.39 (1H, d, J=5.9 Hz), 1.82-1.99 (2H, m),2.02-2.15 (2H, m), 2.35-2.50 (2H, m), 2.64-2.80 (1H, m), 3.77 (3H, s),3.87-3.97 (2H, m), 4.66 (1H, m), 5.12 (2H, s), 6.52 (1H, dd, J=3.3, 1.9Hz), 6.93-7.03 (3H, m), 7.11 (1H, d, J=3.1 Hz), 7.47-7.53 (2H, m), 7.72(2H, d, J=8.8 Hz), 7.82 (1H, d, J=8.1 Hz).

Step 2

A 2M aqueous solution of lithium hydroxide (0.06 mL, 0.120 mmol) wasadded to a suspension of the compound (19) (32 mg, 0.060 mmol) in amixture of methanol (1.0 mL) and tetrahydrofuran (1.0 mL) and stirred atroom temperature for 4 hours, and then a 2M aqueous solution of lithiumhydroxide (0.06 mL, 0.120 mmol) was further added and stirred at roomtemperature for 2.5 hours. The reaction solution was diluted with waterand acidified by adding a 0.5M aqueous solution of citric acid. Theproduct was extracted with ethyl acetate, and the extract was washedwith water, dried and concentrated. The residue was crystallized fromethyl acetate to give the compound I-26 (23 mg, 74% yield).

¹H-NMR (CDCl₃) δ ppm: 1.39 (1H, d, J=6.1 Hz), 1.79-1.95 (2H, m),1.96-2.10 (2H, m), 2.35-2.49 (2H, m), 2.62-2.76 (1H, m), 3.87-3.96 (2H,m), 4.65 (1H, m), 5.08 (2H, s), 6.55 (1H, dd, J=3.5, 1.8 Hz), 6.90 (1H,s), 6.98 (2H, d, J=8.9 Hz), 7.14 (1H, d, J=3.8 Hz), 7.50-7.56 (2H, m),7.71 (2H, d, J=8.9 Hz), 7.89 (1H, d, J=8.2 Hz).

The compounds of (I-1) to (I-3), (I-5) to (I-12), (I-15) to (I-25),(I-27) to (I-32) were synthesized in the same manner as set forth above.The chemical structures and physical properties thereof are shown inTables 6-16.

In addition, the compound of (II-1) to (II-59), (II-61) to (II-74),(II-76) to (II-80), (II-82) to (II-93), (II-95), (II-97) to (II-105),(II-110) to (II-149) can be synthesized in the same manner as set forthabove. Their structures are shown in Tables 17-29.

TABLE 6

            Com- pound No.

     

I-1

I-2

I-3

I-4

I-6

I-7

TABLE 7

                Compound No.

     

I-8 

I-11

I-12

I-13

I-14

I-15

TABLE 8

                Compound No.

     

I-16

I-17

I-18

I-19

I-20

I-21

TABLE 9

                Compound No.

     

I-22

I-23

I-24

I-25

I-26

I-27

TABLE 10

                Compound No.

     

I-28

I-29

I-30

I-31

I-32

TABLE 11

            Com- pound No.

     

I-5

I-9

TABLE 12

              Com- pound No.

I-10

TABLE 13 Compound No. 1H-NMR (DMSO-d6) δ ppm I-1 1.32 (d, 6H, J = 6.0Hz), 1.59-1.73 (m, 2H), 2.01 (brd, 2H), 2.37 (brt, 2H), 2.78 (m, 1H),3.74 (brd, 2H), 4.76 (m, 1H), 4.94 (s, 2H), 7.04 (dd, 1H, J = 4.5, 7.8Hz), 7.13-7.18 (m, 2H), 7.29 (s, 1H), 7.66-7.71 (m, 2H), 7.95 (dd, 1H, J= 1.8, 7.8 Hz), 8.18 (dd, 1H, J = 1.8, 4.5 Hz), 12.91 (brs, 1H) I-21.59-1.78 (m, 2H), 2.02 (brd, 2H), 2.36 (brt, 2H), 2.77 (m, 1H), 3.75(brd, 2H), 3.88 (s, 3H), 4.95 (s, 2H), 7.04 (dd, 1H, J = 4.5, 7.8 Hz),7.17-7.22 (m, 2H), 7.29 (s, 1H), 7.70-7.75 (m, 2H), 7.95 (dd, 1H, J =1.5, 7.8 Hz), 8.18 (dd, 1H, J = 1.5, 4.5 Hz), 12.94 (br, 1H) I-3 1.73(t, 3H, J = 6.9 Hz), 1.59-1.73 (m, 2H), 2.02 (brd, 2H), 2.36 (brt, 2H),2.77 (m, 1H), 3.74 (brd, 2H), 4.15 (q, 2H, J = 6.9 Hz), 4.94 (s, 2H),7.04 (dd, 1H, J = 4.5, 7.8 Hz), 7.14-7.19 (m, 2H), 7.29 (s, 1H),7.68-7.73 (m, 2H), 7.95 (dd, 1H, J = 1.2, 7.8 Hz), 8.18 (dd, 1H, J =1.2, 4.5 Hz), 12.94 (br, 1H) I-4 1.32 (d, 6H, J = 6.0 Hz), 1.58-1.74 (m,2H), 2.00 (brd, 2H), 2.37 (brt, 2H), 2.78 (m, 1H), 3.76 (brd, 2H), 4.76(m, 1H), 5.06 (s, 2H), 7.15 (d, 2H, J = 8.7 Hz), 7.35 (s, 1H), 7.51 (d,1H, J = 5.7 Hz), 7.68 (d, 2H, J = 8.7 Hz), 8.07 (d, 1H, J = 5.7 Hz),8.72 (s, 1H) I-5 1.27 (d, 6H, J = 6.0 Hz), 2.56 (brs, 2H), 3.22 (t-like,2H), 3.69 (brs, 2H), 4.72 (m, 1H), 4.99 (s, 2H), 6.15 (brs, 1H),7.09-7.16 (m, 3H), 7.59 (s, 1H), 7.70-7.75 (m, 2H), 8.20-8.25 (m, 2H),13.00 (br, 1H) I-6 0.94 (t, 3H, J = 7.7 Hz), 1.28 (d, 3H, J = 6.0 Hz),1.55-1.78 (m, 4H), 2.02 (brd, 2H), 2.38 (brt, 2H), 2.78 (m, 1H), 3.74(brd, 2H), 4.54 (m, 1H), 4.94 (s, 2H), 7.04 (dd, 1H, J = 4.8, 7.8 Hz),7.14-7.18 (m, 2H), 7.28 (s, 1H), 7.66-7.71 (m, 2H), 7.96 (dd, 1H, J =1.5, 7.8 Hz), 8.19 (dd, 1H, J = 1.5, 4.8 Hz), 12.91 (brs, 1H) I-7 1.33(d, 6H, J = 6.0 Hz), 1.79 (q, 2H, J = 12.3 Hz), 2.11 (d, 2H, J = 11.4Hz), 2.36 (t, 2H, J = 11.4 Hz), 2.85 (t, 1H, J = 11.4 Hz), 3.73 (d, 2H,J = 11.7 Hz), 4.76 (m, 1H), 4.99 (s, 2H), 7.09-7.16 (m, 3H), 7.39 (s,1H), 7.68 (d, 2H, J = 9.0 Hz), 7.79 (d, 1H, J = 8.4 Hz), 8.29 (d, 1H, J= 4.5 Hz) I-8 1.37 (t, 3H, J = 6.9 Hz), 1.78 (q, 2H, J = 12.3 Hz), 2.10(d, 2H, J = 10.8 Hz), 2.35 (t, 2H, J = 11.4 Hz), 2.84 (t, 1H, J = 11.4Hz), 3.73 (d, 2H, J = 11.1 Hz), 4.14 (q, 2H, J = 6.9 Hz), 5.00 (s, 2H),7.14-7.17 (m, 3H), 7.42 (brs, 1H), 7.69 (d, 2H, J = 8.4 Hz), 7.84 (d,1H, J = 8.1 Hz), 8.31 (d, 1H, J = 3.9 Hz) I-9 1.28 (d, 6H, J = 6.3 Hz),2.58 (brs, 2H), 3.22 (t, 2H, J = 5.7 Hz), 3.71 (brs, 2H), 4.69-4.77 (m,1H), 5.02 (s, 2H), 7.11-7.18 (m, 4H), 7.63 (s, 1H), 7.72 (d, 2H, J = 8.7Hz), 7.84 (dd, 1H, J = 1.2, 8.4 Hz), 8.37 (dd, 1H, J = 1.5, 4.5 Hz) I-101.29 (d, 6H, J = 6.0 Hz), 1.44-2.00 (m, 4H), 2.27-2.39 (m, 2H), 3.10 (m,1H), 3.63 (brd, 1H), 3.76 (brd, 1H), 4.72 (m, 1H), 4.96 (s, 2H),7.07-7.12 (m, 3H), 7.35 (s, 1H), 7.62-7.67 (m, 2H), 8.01 (dd, 1H, J =1.5, 7.8 Hz), 8.22 (dd, 1H, J = 1.5, 4.8 Hz), 12.94 (br, 1H)

TABLE 14 Compound No. 1H-NMR (DMSO-d6) δ ppm I-11 1.35 (d, 6H, J = 6.0Hz), 1.61-1.75 (m, 2H), 2.04 (brd, 2H), 2.43-2.50 (m, 2H), 2.83 (m, 1H),3.77 (brd, 2H), 4.95 (s, 2H), 5.36 (m, 1H), 6.99 (dd, 1H, J = 0.6, 9.0Hz), 7.05 (dd, 1H, J = 4.5, 7.8 Hz), 7.30 (s, 1H), 7.96 (dd, 1H, J =1.5, 7.8 Hz), 8.02 (dd, 1H, J = 2.7, 9.0 Hz), 8.19 (dd, 1H, J = 1.5, 4.5Hz), 8.56 (dd, 1H, J = 0.6, 2.7 Hz), 12.90 (br, 1H) I-12 1.31 (6H, d, J= 6 Hz), 1.60-1.70 (2H, m), 2.07 (2H, d, J = 11.4 Hz), 2.31 (2H, t, J =11.7 Hz), 3.0-3.5 (1H, m), 3.76 (2H, d, J = 10.8 Hz), 4.71 (2H, s),4.71-4.77 (1H, m), 7.09 (1H, d, J = 5.1 Hz), 7.14 (2H, d, J = 8.7 Hz),7.40 (1H, s), 7.67 (2H, d, J = 8.7 Hz), 8.08 (1H, d, J = 5.1 Hz) I-131.31 (6H, d, J = 6 Hz), 1.80-1.90 (2H, m), 1.99-2.31 (2H, m), 2.35 (2H,t, J = 11.1 Hz), 2.70-2.80 (1H, m), 3.73 (2H, d, J = 12 Hz), 4.70-4.80(1H, m), 4.89 (2H, s), 7.14 (2H, d, J = 8.7 Hz), 7.21 (1H, d, J = 8.1Hz), 7.30 (1H, s), 7.67(2H, d, J = 9 Hz), 7.94 (1H, d, J = 8.1 Hz) I-141.31 (6H, d, J = 6 Hz), 1.55-1.70 (2H, m), 1.95-2.05 (2H, m), 2.36 (2H,t, J = 11.4 Hz), 2.65-2.75 (2H, m), 3.73 (2H, d, J = 11.4 Hz), 3.83 (3H,s), 4.70-4.80 (1H, m), 4.85 (2H, s), 6.48 (1H, d, J = 8.4 Hz), 7.01 (1H,s), 7.14 (2H, d, J = 8.7 Hz) 7.68 (2H, d, J = 8.7 Hz), 7.84 (1H, d, J =8.4 Hz) I-15 1.31 (2H, d, J = 6 Hz), 1.55-1.65 (2H, m), 1.96 (2H, d, J =14.4 Hz), 2.32 (2H, t, J = 11.4 Hz), 2.69 (1H, brs), 4.75 (1H, m), 4.98(2H, s), 6.57 (1H, d, J = 9 Hz), 6.96 (1H, d, J = 9 Hz), 7.13 (2H, d, J= 8.7 Hz), 7.68 (2H, d, J = 8.7 Hz), 8.10-8.15 (1H, m) I-16 1.32 (6H, d,J = 6.0 Hz), 1.69 (2H, m), 2.03 (2H, m), 2.39 (2H, m), 2.80 (1H, m),3.75 (2H, m), 4.77(1H, tt, J = 6.0 Hz, 6.0 Hz), 5.02 (2H, s), 7.16 (2H,d, J = 8.7 Hz), 7.32 (1H, s), 7.44-7.49 (2H, m), 7.64 (1H, d, J = 8.1Hz), 7.69 (2H, d, J = 8.7 Hz), 8.03 (1H, d, J = 8.1 Hz), 8.08-8.11 (2H,m). I-17 1.30 (6H, d, J = 6.0 Hz), 1.68 (2H, m), 2.38 (2H, m), 2.80 (1H,m), 3.75 (2H, m), 4.77 (1H, tt, J = 6.0 Hz, 6.0 Hz), 5.02 (2H, s), 7.16(2H, d, J = 9.0 Hz), 7.26-7.32 (2H, m), 7.64 (2H, d, J = 8.1 Hz), 7.69(2H, d, J = 9.0 Hz), 8.04 (1H, d, J = 8.1 Hz), 8.14 (2H, m). I-18 1.32(6H, d, J = 6.0 Hz), 1.69 (2H, m), 2.39 (2H, m), 2.83 (1H, m), 3.76 (2H,m), 4.77 (1H, tt, J = 6.0 Hz, 6.0 Hz), 5.07 (2H, s), 7.16 (2H, d, J =9.0 Hz), 7.41 (1H, s), 7.67-7.75 (3H, m), 7.80 (1H, d, J = 8.1 Hz), 8.14(1H, d, J = 8.1 Hz), 8.69 (1H, m), 8.72 (1H, m), 9.38 (1H, m). I-19 1.33(6H, d, J = 6.0 Hz), 1.72 (2H, m), 2.05 (2H, m), 2.39 (2H, m), 2.83 (1H,m), 3.77 (2H, m), 4.77 (1H, tt, J = 6.0 Hz, 6.0 Hz), 5.10 (2H, s), 7.17(2H, d, J = 9.0 Hz), 7.44 (1H, s), 7.70 (2H, d, J = 9.0 Hz), 8.05 (1H,m), 8.11 (1H, d, J = 8.1 Hz), 8.17 (1H, d, J = 8.1 Hz), 8.50 (1H, m),8.69 (1H, m), 13.10 (1H, br).

TABLE 15 Compound No. 1H-NMR (DMSO-d6) δ ppm I-20 1.33 (6H, d, J = 6.0Hz), 1.70 (2H, m), 2.04 (2H, m), 2.39 (2H, m), 2.82 (1H, m), 3.76 (2H,m), 4.77 (1H, tt, J = 6.0 Hz, 6.0 Hz), 5.00 (2H, s), 7.16 (2H, d, J =9.0 Hz), 7.43 (1H, s), 7.70 (2H, d, J = 9.0 Hz), 7.77 (1H, d, J = 3.3Hz), 7.88 (1H, d, J = 8.1 Hz), 7.92 (1H ,d, J = 3.3 Hz), 8.10 (1H, d, J= 8.1 Hz), 13.00 (1H, br). I-21 1.39 (d, J = 6.3 Hz, 6H), 1.50 (s, 3H),1.80-1.85 (m, 2H), 2.00-2.10 (m, 2H), 2.38-2.42 (m, 2H), 2.60-2.65 (m,1H), 3.90 (d, J = 11.7 Hz, 2H), 4.60-4.65 (m, 1H), 4.90 (s, 2H), 6.77(s, 1H), 6.98 (d, J = 8.7 Hz, 2H), 7.69-7.82 (m, 4H). I-22 1.39 (d, J =6.1 Hz, 6H), 1.76-2.12 (m, 7H), 2.34-2.45 (m, 2H), 2.52-2.67 (m, 1H),3.40-3.60 (m, 4H), 3.89 (brd, J = 11.7 Hz, 2H), 4.65 (tt, J = 6.1, 6.1Hz, 1H), 4.90 (brs, 2H), 6.27 (d, J = 8.8 Hz, 1H), 6.50 (s, 1H), 6.98(d, J = 8.8 Hz, 2H), 7.65-7.31 (m, 1H), 7.71 (d, J = 7.7 Hz, 2H) I-231.39 (d, J = 5.9 Hz, 6H), 1.76-1.93 (m, 2H), 2.00-2.20 (m, 4H),2.34-2.45 (m, 2H), 2.62-2.76 (m, 3H), 3.90 (d, J = 11.3 Hz, 2H), 4.13(t, J = 7.2 Hz, 2H), 4.65 (tt, J = 5.9, 5.9 Hz, 1H), 4.94(s, 2H), 6.85(s, 1H), 6.98 (d, J = 9.1 Hz, 2H), 7.71 (d, J = 9.1 Hz, 2H), 7.82 (d, J= 8.8 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H) I-24 1.31 (d, J = 6.0 Hz, 6H),1.53-1.74 (m, 2H), 1.92-2.07 (m, 2H), 2.07 (s, 3H), 2.28-2.43 (m, 2H),2.65-2.81 (m, 1H), 3.68-3.78 (m, 2H), 4.76 (tt, J = 6.0, 6.0 Hz, 1H),4.87 (brs, 2H), 7.11-7.18 (m, 3H), 7.68 (d, J = 8.9 Hz, 2H), 7.82 (br-d,J = 8.5 Hz, 1H), 7.71 (dd, J = 8.5, 3.3 Hz, 2H) I-25 1.39 (6H, d, J =5.6 Hz), 1.55-1.75 (2H, m), 1.95-2.09 (2H, m), 2.27-2.45 (2H, m),2.65-2.85 (1H, m), 3.65-3.80 (2H, m), 4.67-4.85 (1H, m), 4.97 (2H, s),7.04 (1H, s), 7.16 (2H, J = 7.2 Hz), 7.25 (1H, s), 7.40 (1H, d, J = 8.0Hz), 7.63-7.77 (3H, m), 7.96 (1H, d, J = 7.2 Hz), 8.28 (1H, s), 12.90(1H, brs). I-26 1.39 (1H, d, J = 6.1 Hz), 1.79-1.95 (2H, m), 1.96-2.10(2H, m), 2.35-2.49 (2H, m), 2.62-2.76 (1H, m), 3.87-3.96 (2H, m), 4.65(1H, tt, J = 6.1, 6.1 Hz), 5.08 (2H, s), 6.55 (1H, dd, J = 3.5, 1.8 Hz),6.90 (1H, s), 6.98 (2H, d, J = 8.9 Hz), 7.14 (1H, d, J = 3.8 Hz),7.50-7.56 (2H, m), 7.71 (2H, d, J = 8.9 Hz), 7.89 (1H, d, J = 8.2 Hz).

TABLE 16 Compound No. 1H-NMR (DMSO-d6) δ ppm I-27 1.31 (6H, d, J = 6.3Hz), 1.50-1.70 (2H, m), 1.96 (2H, d, J = 12 HZ), 2.33 (2H, t, J = 11.7Hz), 2.63-2.73 (1H, m), 3.67 (3H, s), 3.65-3.73 (2H, m), 4.71-4.80 (1H,m), 5.02 (2H, s), 6.41 (1H, d, J = 8.1 Hz), 6.85 (1H, s), 7.15 (2H, d, J= 9 Hz), 7.67 (2H, d, J = 9 Hz), 7.86 (1H, br). I-28 0.26-0.28 (2H, m),0.47-0.50 (2H, m), 1.06-1.10 (1H, m), 1.72 (6H, d, J = 6 Hz), 1.55-1.65(2H m), 1.96-1.99(2H, m), 2.34 (2H, t, J = 12 Hz), 2.63-2.73 (1H, m),3.20 (2H, d, J = 7.2 Hz), 3.73 (2H, d, J = 11.7 Hz), 4.73-4.78 (1H, m),4.92 (2H, s), 6.54(1H, d, J = 8.4 Hz), 6.90 (1H, s), 7.14 (2H, d, J = 9Hz), 7.70 (2H, d, J = 9 Hz), 7.90-7.95 (1H, m). I-29 1.39 (d, J = 6.1Hz, 6H), 1.40 (t, J = 7.0 Hz, 3H), 1.77-1.94 (m, 2H), 2.34-2.46 (m, 2H),3.82-3.95 (1H, m), 4.34 (q, J = 7.0 Hz, 2H), 4.65 (qq, J = 6.1 Hz, 1H),4.92 (s, 2H), 6.53 (d, J = 8.6 Hz, 2H), 6.70 (s, 1H), 6.98 (d, J = 8.9Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.6 Hz, 1H) I-30 1.41(6H, d, J = 5.9 Hz), 1.78-1.94 (2H, m), 2.00-2.11 (2H, m), 2.42 (2H, t,J = 10.9 Hz), 2.61-2.74 (1H, m), 3.46 (3H, s), 3.78 (2H, t, J = 4.7 Hz),3.92 (2H, d, J = 11.6 Hz), 4.49 (2H, t, J = 4.7 Hz), 4.67 (1H, tt, J =12.1. 6.1 Hz), 4.94 (2H, s), 6.62 (1H, d, J = 8.4 Hz), 6.74 (1H, s),7.00 (2H, d, J = 8.9 Hz), 7.70-7.77 (3H, m). I-31 1.39 (6H, d, J = 6.0Hz), 1.75-1.93 (2H, m), 1.98-2.08 (2H, m), 2.32-2.45 (2H, m), 2.59-2.71(1H, m), 3.89 (2H, d, J = 12.1 Hz), 4.65 (1H, tt, J = 12.0, 6.0 Hz),4.93 (2H, s), 5.37 (2H, s), 6.60 (1H, d, J = 8.5 Hz), 6.71 (1H, s), 6.98(2H, d, J = 8.4 Hz), 7.27-7.38 (3H, m), 7.45 (2H, dd, J = 7.2, 1.5 Hz),7.68-7.74 (3H, m). I-32 1.34 (5H, d, J = 6.1 Hz), 1.55-1.71 (2H, m),1.93-2.05 (2H, m), 2.37 (2H, t, J = 11.3 Hz), 2.62-2.78 (1H, m), 3.75(2H, d, J = 11.4 Hz), 4.73-4.84 (3H, m), 6.33 (1H, d, J = 8.3 Hz), 6.92(1H, s), 7.17 (2H, d, J = 8.9 Hz), 7.70 (2H, d, J = 8.9 Hz), 7.77 (1H,d, J = 8.3 Hz).

TABLE 17 Comd. No. Structure II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

 II-10

 II-11

 II-12

TABLE 18 Comd. No. Structure II-13

II-14

II-15

II-16

II-17

II-18

II-19

II-20

II-21

II-22

II-23

II-24

TABLE 19 Comd. No. Structure II-25

II-26

II-27

II-28

II-29

II-30

II-31

II-32

II-33

II-34

TABLE 20 Comd. No. Structure II-35

II-36

II-37

II-38

II-39

II-40

II-41

II-42

II-43

II-44

TABLE 21 Comd. No. Structure II-45

II-46

II-47

II-48

II-49

II-50

II-51

II-52

II-53

II-54

II-55

II-56

TABLE 22 Comd. No. Structure II-57

II-58

II-59

II-61

II-62

II-63

II-64

II-65

II-66

II-67

II-68

II-69

TABLE 23 Comd. No. Structure II-70

II-71

II-72

II-73

II-74

II-76

II-77

II-78

II-79

II-80

II-82

II-83

TABLE 24 Comd. No. Structure II-84

II-85

II-86

II-87

II-88

II-89

II-90

II-91

II-92

II-93

TABLE 25 Comd. No. Structure II-95 

II-97 

II-98 

II-99 

II-100

II-101

II-102

II-103

II-104

II-105

TABLE 26 Comd. No. Structure II-110

II-111

II-112

II-113

II-114

II-115

II-116

II-117

II-118

II-119

TABLE 27 Comd. No. Structure II-120

II-121

II-121

II-123

II-124

II-125

II-126

II-127

II-128

II-129

II-130

II-131

TABLE 28 Comd. No. Structure II-132

II-133

II-134

II-135

II-136

II-137

II-138

II-139

II-140

II-141

TABLE 29 Comd. No. Structure II-142

II-143

II-144

II-145

II-146

II-147

II-148

II-149

II-150

II-151

II-152

II-153

In addition, the compound of the next formula (IB):

wherein R^(1A) and R^(2A) are independently a hydrogen atom, a fluorineatom, a chlorine atom, a bromine atom, methyl, ethyl, trifluoromethyl,methyloxy, ethyloxy, difluoromethyloxy, trifluoromethyloxy, methylthio,methylsulfinyl, methylsulfonyl, amino, methylamino, acetylamino, cyano,nitro, phenyl, 2-pyridyl, 2-furyl, 2-thienyl, 2-oxazolyl, 2-thiazolyl,pyrrolidino, piperidino, piperazino or morpholino;

R^(3A) is a hydrogen atom, a chlorine atom, a bromine atom, methyl,methyloxy, ethyloxy, allyloxy, propargyloxy, methylthio, methylsulfinyl,methylsulfonyl, amino, methylamino, dimethylamino, acetylamino, acetyl,methyloxycarbonyl, N-methylcarbamoyl, N,N-dimethylcarbamoyl, phenyl,4-fluorophenyl, 2-pyridyl, 3-pyridyl, 2-oxazolyl, 2-thiazolyl,pyrrolidino, piperidino, piperazino, morpholino, cyclopropylmethylamino,t-butoxycarbonylamino, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,5-oxazolyl, a fluorine atom, phenoxy, cyano, nitro, carbamoyl,N-n-propylcarbamoyl, N-phenylcarbamoyl, methyloxycarbonylamino,i-propyloxycarbonylamino, 3-pyridylcarbonylamino, 2-furylcarbonylamino,3-methyloxyphenyl, 4-methyloxyphenyl, 4-cyanophenyl, 4-oxazolyl,5-methyl-2-oxazolyl, 3,4-oxadiazol-2-yl, 5-methyl-3,4-oxadiazol-2-yl,3,4-thiadiazol-2-yl, 5-methyl-3,4-thiadiazol-2-yl, 4-pyridyl,4-methyloxy-3-pyridyl, hydrazinocarbonyl, 1-pyrazolyl,3,4-methylenedioxyphenyl, N-cyclopropylcarbamoyl,4-isooxazolylcarbonylamino, 5-methylisooxazol-3-yl-carbonylamino,trifluoromethyl, or 3-methyloxypropargyl;

R^(5A) is a hydrogen atom or methyl;

R^(6A) is ethyloxy, isopropyloxy, 2,2-difluoromethyloxy orisopropylthio;

R^(7A), R^(7B), R^(7C) and R^(7D) are independently a hydrogen atom afluorine atom or methyl,

can be synthesized in the same manner as set forth above.

Combinations of R^(1A), R^(2A), R^(3A) and R^(5A) (part A) are shown inTables 30-35. Combinations of R^(6A), R^(7A), R^(7B), R^(7C) and R^(7D)(part B) are shown in Tables 36-37.

TABLE 30 No. R^(1A) R^(2A) R^(3A) R^(5A) A-1 H H H H A-2 F H H H A-3 ClH H H A-4 Br H H H A-5 Me H H H A-6 Et H H H A-7 CF3 H H H A-8 OMe H H HA-9 OEt H H H A-10 OCHF₂ H H H A-11 SMe H H H A-12 SOMe H H H A-13 SO₂MeH H H A-14 NH₂ H H H A-15 NHMe H H H A-16 NHAc H H H A-17 CN H H H A-18NO₂ H H H A-19 Ph H H H A-20 2-pyridyl H H H A-21 2-furyl H H H A-222-thienyl H H H A-23 pyrrolidino H H H A-24 piperidino H H H A-25piperazino H H H A-26 morpholino H H H A-27 H F H H A-28 H Cl H H A-29 HBr H H A-30 H Me H H A-31 H Et H H A-32 H CF3 H H A-33 H OMe H H A-34 HOEt H H A-35 H OCHF₂ H H A-36 H SMe H H A-37 H SOMe H H A-38 H SO₂Me H HA-39 H NH₂ H H A-40 H NHMe H H A-41 H NHAc H H A-42 H CN H H A-43 H NO₂H H A-44 H Ph H H A-45 H 2-pyridyl H H A-46 H 2-furyl H H A-47 H2-thienyl H H A-48 H pyrrolidino H H

TABLE 31 No. R^(1A) R^(2A) R^(3A) R^(5A) A-49 H piperidino H H A-50 Hpiperazino H H A-51 H morpholino H H A-52 H H H Me A-53 F H H Me A-54 ClH H Me A-55 Br H H Me A-56 Me H H Me A-57 Et H H Me A-58 CF3 H H Me A-59OMe H H Me A-60 OEt H H Me A-61 OCHF₂ H H Me A-62 SMe H H Me A-63 SOMe HH Me A-64 SO₂Me H H Me A-65 NH₂ H H Me A-66 NHMe H H Me A-67 NHAc H H MeA-68 CN H H Me A-69 NO₂ H H Me A-70 Ph H H Me A-71 2-pyridyl H H Me A-722-furyl H H Me A-73 2-thienyl H H Me A-74 pyrrolidino H H Me A-75piperidino H H Me A-76 piperazino H H Me A-77 morpholino H H Me A-78 H FH Me A-79 H Cl H Me A-80 H Br H Me A-81 H Me H Me A-82 H Et H Me A-83 HCF3 H Me A-84 H OMe H Me A-85 H OEt H Me A-86 H OCHF₂ H Me A-87 H SMe HMe A-88 H SOMe H Me A-89 H SO₂Me H Me A-90 H NH₂ H Me A-91 H NHMe H MeA-92 H NHAc H Me A-93 H CN H Me A-94 H NO₂ H Me A-95 H Ph H Me A-96 H2-pyridyl H Me

TABLE 32 No. R^(1A) R^(2A) R^(3A) R^(5A) A-97 H 2-furyl H Me A-98 H2-thienyl H Me A-99 H pyrrolidino H Me A-100 H piperidino H Me A-101 Hpiperazino H Me A-102 H morpholino H Me A-103 F H Cl H A-104 F H Br HA-105 F H Me H A-106 F H Et H A-107 F H OMe H A-108 F H OEt H A-109 F Hallyloxy H A-110 F H propargyloxy H A-111 F H SMe H A-112 F H SOMe HA-113 F H SO₂Me H A-114 F H NH₂ H A-115 F H NHMe H A-116 F H NMe₂ HA-117 F H NHAc H A-118 F H Ac H A-119 F H COOMe H A-120 F H CONHMe HA-121 F H CONMe₂ H A-122 F H Ph H A-123 F H 4-F-phenyl H A-124 F H2-pyridyl H A-125 F H 3-pyridyl H A-126 F H 2-oxazolyl H A-127 F H2-thiazolyl H A-128 F H pyrrolidino H A-129 F H piperidino H A-130 F Hpiperazino H A-131 Cl H morpholino H A-132 Cl H Cl H A-133 Cl H Br HA-134 Cl H Me H A-135 Cl H Et H A-136 Cl H OMe H A-137 Cl H OEt H A-138Cl H allyloxy H A-139 Cl H propargyloxy H A-140 Cl H SMe H A-141 Cl HSOMe H A-142 Cl H SO₂Me H A-143 Cl H NH₂ H A-144 Cl H NHMe H

TABLE 33 No. R^(1A) R^(2A) R^(3A) R^(5A) A-145 Cl H NMe₂ H A-146 Cl HNHAc H A-147 Cl H Ac H A-148 Cl H COOMe H A-149 Cl H CONHMe H A-150 Cl HCONMe₂ H A-151 Cl H Ph H A-152 Cl H 4-F-phenyl H A-153 Cl H 2-pyridyl HA-154 Cl H 3-pyridyl H A-155 Cl H 2-oxazolyl H A-156 Cl H 2-thiazolyl HA-157 Cl H pyrrolidino H A-158 Cl H piperidino H A-159 Cl H piperazino HA-160 Cl H morpholino H A-161 H Cl OMe H A-162 Br H Cl H A-163 Br H Br HA-164 Br H Me H A-165 Br H Et H A-166 Br H OMe H A-167 Br H OEt H A-168Br H allyloxy H A-169 Br H propargyloxy H A-170 Br H SMe H A-171 Br HSOMe H A-172 Br H SO₂Me H A-173 Br H NH₂ H A-174 Br H NHMe H A-175 Br HNMe₂ H A-176 Br H NHAc H A-177 Br H Ac H A-178 Br H COOMe H A-179 Br HCONHMe H A-180 Br H CONMe₂ H A-181 Br H Ph H A-182 Br H 4-F-phenyl HA-183 Br H 2-pyridyl H A-184 Br H 3-pyridyl H A-185 Br H 2-oxazolyl HA-186 Br H 2-thiazolyl H A-187 Br H pyrrolidino H A-188 Br H piperidinoH A-189 Br H piperazino H A-190 Br H morpholino H A-191 H Br OMe H A-192Me H Cl H A-193 Me H Br H

TABLE 34 No. R^(1A) R^(2A) R^(3A) R^(5A) A-194 Me H Me H A-195 Me H Et HA-196 Me H OMe H A-197 Me H OEt H A-198 Me H allyloxy H A-199 Me Hpropargyloxy H A-200 Me H SMe H A-201 Me H SOMe H A-202 Me H SO₂Me HA-203 Me H NH₂ H A-204 Me H NHMe H A-205 Me H NMe₂ H A-206 Me H NHAc HA-207 Me H Ac H A-208 Me H COOMe H A-209 Me H CONHMe H A-210 Me H CONMe₂H A-211 Me H Ph H A-212 Me H 4-F-phenyl H A-213 Me H 2-pyridyl H A-214Me H 3-pyridyl H A-215 Me H 2-oxazolyl H A-216 Me H 2-thiazolyl H A-217Me H pyrrolidino H A-218 Me H piperidino H A-219 Me H piperazmo H A-220Me H morpholino H A-221 H H Cl H A-222 H H Br H A-223 H H Me H A-224 H HEt H A-225 H H OMe H A-226 H H OEt H A-227 H H allyloxy H A-228 H Hpropargyloxy H A-229 H H SMe H A-230 H H SOMe H A-231 H H SO₂Me H A-232H H NH₂ H A-233 H H NHMe H A-234 H H NMe₂ H A-235 H H NHAc H A-236 H HAc H A-237 H H COOMe H A-238 H H CONHMe H A-239 H H CONMe₂ H A-240 H HPh H A-241 H H 4-F-phenyl H

TABLE 35 No. R^(1A) R^(2A) R^(3A) R^(5A) A-242 H H 2-pyridyl H A-243 H H3-pyridyl H A-244 H H 2-oxazolyl H A-245 H H 2-thiazolyl H A-246 H Hpyrrolidino H A-247 H H piperidino H A-248 H H piperazmo H A-249 H Hmorpholino H A-250 H H NH(cyclopropylmethyl) H A-251 H H NHBoc H A-252 HH 2-furyl H A-253 H H 3-furyl H A-254 H H 2-thienyl H A-255 H H3-thienyl H A-256 H H 5-oxazolyl H A-257 H F OMe H A-258 H Me OMe HA-259 H H F H A-260 H H OPh H A-261 H H CN H A-262 H H NO₂ H A-263 H HCONH₂ H A-264 H H CONHn-Pr H A-265 H H CONHPh H A-266 H H NHCOOMe HA-267 H H NHCOOi-Pr H A-268 H H NHCO(3-pyridyl) H A-269 H HNHCO(2-furyl) H A-270 H H 3-methyloxyphenyl H A-271 H H4-methyloxyphenyl H A-272 H H 4-cyanophenyl H A-273 H H 4-oxazolyl HA-274 H H 5-Me-2-oxazolyl H A-275 H H 3,4-oxadiazol-2yl H A-276 H H5-Me-3,4-oxadiazol-2yl H A-277 H H 3,4-thiadiazol-2yl H A-278 H H5-Me-3,4-thiadiazol-2yl H A-279 H H 4-pyridyl H A-280 H H4-methyloxy3-pyridyl H A-281 H H CONHNH₂ H A-282 H H 1-pyrazolyl H A-283H H 3,4-methylenedioxy- H phenyl A-284 H H CONH(cyclopropyl) H A-285 H HNHCO(4-isoxazolyl) H A-286 H H NHCO(5-Me-isoxazol- H 3-yl) A-287 H H CF₃H A-288 H H 3-methyloxypropargyl H

TABLE 36 No. R^(6A) R^(7A) R^(7B) R^(7C) R^(7D) B-1 OEt H H H H B-2OCHMe₂ H H H H B-3 OCHF₂ H H H H B-4 SCHMe₂ H H H H B-5 OEt F H H H B-6OEt Me H H H B-7 OEt H F H H B-8 OEt H Me H H B-9 OEt F F H H B-10 OEt FH F H B-11 OEt F H H F B-12 OEt F Me H H B-13 OEt F H Me H B-14 OEt F HH Me B-15 OEt Me F H H B-16 OEt Me H F H B-17 OEt Me H H F B-18 OEt MeMe H H B-19 OEt Me H Me H B-20 OEt Me H H Me B-21 OCHMe₂ F H H H B-22OCHMe₂ Me H H H B-23 OCHMe₂ H F H H B-24 OCHMe₂ H Me H H B-25 OCHMe₂ F FH H B-26 OCHMe₂ F H F H B-27 OCHMe₂ F H H F B-28 OCHMe₂ F Me H H B-29OCHMe_(a) F H Me H B-30 OCHMe₂ F H H Me B-31 OCHMe₂ Me F H H B-32 OCHMe₂Me H F H B-33 OCHMe₂ Me H H F B-34 OCHMe₂ Me Me H H B-35 OCHMe₂ Me H MeH B-36 OCHMe₂ Me H H Me B-37 OCHF₂ F H H H B-38 OCHF₂ Me H H H

TABLE 37 No. R^(6A) R^(7A) R^(7B) R^(7C) R^(7D) B-39 OCHF₂ H F H H B-40OCHF₂ H Me H H B-41 OCHP₂ F F H H B-42 OCHF₂ F H F H B-43 OCHF₂ F H H FB-44 OCHF₂ F Me H H B-45 OCHF₂ F H Me H B-46 OCHF₂ F H H Me B-47 OCHF₂Me F H H B-48 OCHF₂ Me H F H B-49 OCHF₂ Me H H F B-50 OCHF₂ Me Me H HB-51 OCHF₂ Me H Me H B-52 OCHF₂ Me H H Me B-53 SCHMe₂ F H H H B-54SCHMe₂ Me H H H B-55 SCHMe₂ H F H H B-56 SCHMe₂ H Me H H B-57 SCHMe₂ F FH H B-58 SCHMe₂ F H F H B-59 SCHMe₂ F H H F B-60 SCHMe₂ F Me H H B-61SCHMe₂ F H Me H B-62 SCHMe₂ F H H Me B-63 SCHMe₂ Me F H H B-64 SCHMe₂ MeH F H B-65 SCHMe₂ Me H H F B-66 SCHMe₂ Me Me H H B-67 SCHMe₂ Me H Me HB-68 SCHMe₂ Me H H Me

Compounds of the formula (IB) are shown below; (No. of the compound,part A, part B), (IB-2,A-2,B-2), (IB-3,A-3,B-2), (IB-4,A-4,B-2),(IB-5,A-5,B-2), (IB-6,A-6,B-2), (IB-7,A-7,B-2), (IB-8,A-8,B-2),(IB-9,A-9,B-2), (IB-10,A-10,B-2), (IB-11,A-11,B-2), (IB-12,A-12,B-2),(IB-13,A-13,B-2), (IB-14,A-14,B-2), (IB-15,A-15,B-2), (IB-16,A-16,B-2),(IB-17,A-17,B-2), (IB-18,A-18,B-2), (IB-19,A-19,B-2), (IB-20,A-20,B-2),(IB-21,A-21,B-2), (IB-22,A-22,B-2), (IB-23, A-23,B-2), (IB-24,A-24,B-2),(IB-25,A-25,B-2), (IB-26,A-26,B-2), (IB-27,A-27,B-2), (IB-28,A-28,B-2),(IB-29,A-29,B-2), (IB-30,A-30,B-2), (IB-31,A-31,B-2), (IB-32,A-32,B-2),(IB-33,A-33,B-2), (IB-34,A-34,B-2), (IB-35,A-35,B-2), (IB-36,A-36,B-2),(IB-37,A-37,B-2), (IB-38,A-38,B-2), (IB-39,A-39,B-2), (IB-40,A-40,B-2),(IB-41,A-41,B-2), (IB-42,A-42,B-2), (IB-43,A-43,B-2), (IB-44,A-44,B-2),(IB-45, A-45,B-2), (IB-46,A-46,B-2), (IB-47,A-47,B-2), (IB-48,A-48,B-2),(IB-49,A-49,B-2), (IB-50,A-50,B-2), (IB-51,A-51,B-2), (IB-52,A-52,B-2),(IB-53,A-53,B-2), (IB-54,A-54,B-2), (IB-55,A-55,B-2), (IB-56,A-56,B-2),(IB-57,A-57,B-2), (IB-58,A-58,B-2), (IB-59,A-59,B-2), (IB-60,A-60,B-2),(IB-61,A-61,B-2), (IB-62,A-62,B-2), (IB-63,A-63,B-2), (IB-64,A-64,B-2),(IB-65,A-65,B-2), (IB-66,A-66,B-2), (IB-67, A-67,B-2), (IB-68,A-68,B-2),(IB-69,A-69,B-2), (IB-70,A-70,B-2), (IB-71,A-71,B-2), (IB-72,A-72,B-2),(IB-73,A-73,B-2), (IB-74,A-74,B-2), (IB-75,A-75,B-2), (IB-76,A-76,B-2),(IB-77,A-77,B-2), (IB-78,A-78,B-2), (IB-79,A-79,B-2), (IB-80,A-80,B-2),(IB-81,A-81,B-2), (IB-82,A-82,B-2), (IB-83,A-83,B-2), (IB-84,A-84,B-2),(IB-85,A-85,B-2), (IB-86,A-86,B-2), (IB-87,A-87,B-2), (IB-88,A-88,B-2),(IB-89, A-89,B-2), (IB-90,A-90,B-2), (IB-91,A-91,B-2), (IB-92,A-92,B-2),(IB-93,A-93,B-2), (IB-94,A-94,B-2), (IB-95,A-95,B-2), (IB-96,A-96,B-2),(IB-97,A-97,B-2), (IB-98,A-98,B-2), (IB-99,A-99,B-2),(IB-100,A-100,B-2), (IB-101,A-101,B-2), (IB-102,A-102,B-2),(IB-103,A-103,B-2), (IB-104,A-104,B-2), (IB-105,A-105,B-2),(IB-106,A-106,B-2), (IB-107,A-107,B-2), (IB-108,A-108,B-2),(IB-109,A-109,B-2), (IB-110,A-110,B-2), (IB-111,A-111,B-2),(IB-112,A-112,B-2), (IB-113,A-113,B-2), (IB-114,A-114,B-2),(IB-115,A-115,B-2), (IB-116,A-116,B-2), (IB-117,A-117, B-2),(IB-118,A-118,B-2), (IB-119,A-119,B-2), (IB-120,A-120,B-2),(IB-121,A-121,B-2), (IB-122,A-122,B-2), (IB-123,A-123,B2),(IB-124,A-124,B-2), (IB-125, A-125,B-2), (IB-126,A-126,B-2),(IB-127,A-127,B-2), (IB-128,A-128,B-2), (IB-129,A-129,B-2),(IB-130,A-130,B-2), (IB-131,A-131,B-2), (IB-132,A-132,B-2),(IB-133,A-133,B-2), (IB-134,A-134,B-2), (IB-135,A-135,B-2),(IB-136,A-136,B-2), (IB-137,A-137,B-2), (IB-138,A-138,B-2),(IB-139,A-139,B-2), (IB-140,A-140,B-2), (IB-141,A-141,B-2),(IB-142,A-142,B-2), (IB-143,A-143,B-2), (IB-144,A-144, B-2),(IB-145,A-145,B-2), (IB-146,A-146,B-2), (IB-147,A-147,B-2),(IB-148,A-148,B-2), (IB-149,A-149,B-2), (IB-150,A-150,B-2),(IB-151,A-151,B-2), (IB-152, A-152,B-2), (IB-153,A-153,B-2),(IB-154,A-154,B-2), (IB-155,A-155,B-2), (IB-156,A-156,B-2),(IB-157,A-157,B-2), (IB-158,A-158,B-2), (IB-159,A-159,B-2),(IB-160,A-160,B-2), (IB-161,A-161,B-2), (IB-162,A-162,B-2),(IB-163,A-163,B-2), (IB-164,A-164,B-2), (IB-165,A-165,B-2),(IB-166,A-166,B-2), (IB-167,A-167,B-2), (IB-168,A-168,B-2),(IB-169,A-169,B-2), (IB-170,A-170,B-2), (IB-171,A-171, B-2),(IB-172,A-172,B-2), (IB-173,A-173,B-2), (IB-174,A-174,B-2),(IB-175,A-175,B-2), (IB-176,A-176,B-2), (IB-177,A-177,B-2),(IB-178,A-178,B-2), (IB-179, A-179,B-2), (IB-180,A-180,B-2),(IB-181,A-181,B-2), (IB-182,A-182,B-2), (IB-183,A-183,B-2),(IB-184,A-184,B-2), (IB-185,A-185,B-2), (IB-186,A-186,B-2),(IB-187,A-187,B-2), (IB-188,A-188,B-2), (IB-189,A-189,B-2),(IB-190,A-190,B-2), (IB-191,A-191,B-2), (IB-192,A-192,B-2),(IB-193,A-193,B-2), (IB-194,A-194,B-2), (IB-195,A-195,B-2),(IB-196,A-196,B-2), (IB-197,A-197,B-2), (IB-198,A-198, B-2),(IB-199,A-199,B-2), (IB-200,A-200,B-2), (IB-201,A-201,B-2),(IB-202,A-202,B-2), (IB-203,A-203,B-2), (IB-204,A-204,B-2),(IB-205,A-205,B-2), (IB-206, A-206,B-2), (IB-207,A-207,B-2),(IB-208,A-208,B-2), (IB-209,A-209,B-2), (IB-210,A-210,B-2),(IB-211,A-211,B-2), (IB-212,A-212,B-2), (IB-213,A-213,B-2),(IB-214,A-214,B-2), (IB-215,A-215,B-2), (IB-216,A-216,B-2),(IB-217,A-217,B-2), (IB-218,A-218,B-2), (IB-219,A-219,B-2),(IB-220,A-220,B-2), (IB-224,A-224 B-2), (IB-226,A-226,B-2),(IB-233,A-233,B-2), (IB-238,A-238,B-2), (IB-239,A-239, B-2),(IB-244,A-244,B-2), (IB-246,A-246,B-2), (IB-247,A-247,B-2),(IB-248,A-248,B-2), (IB-251,A-2,B-21), (IB-252,A-3,B-21),(IB-253,A-4,B-21), (IB-254,A-5, B-21), (IB-255,A-6,B-21),(IB-256,A-7,B-21), (IB-257,A-8,B-21), (IB-258,A-9,B-21),(IB-259,A-10,B-21), (IB-260,A-11,B-21), (IB-261,A-12,B-21),(IB-262,A-13, B-21), (IB-263,A-14,B-21), (IB-264,A-15,B-21),(IB-265,A-16,B-21), (IB-266,A-17,B-21), (IB-267,A-18,B-21),(IB-268,A-19,B-21), (IB-269,A-20,B-21), (IB-270, A-21,B-21),(IB-271,A-22,B-21), (IB-272,A-23,B-21), (IB-273,A-24,B-21),(IB-274,A-25,B-21), (IB-275,A-26,B-21), (IB-276,A-27,B-21),(IB-277,A-28,B-21), (I B-278,A-29,B-21), 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(IB-1195,A-199,B-24),(IB-1196,A-200,B-24), (IB-1197,A-201,B-24), (IB-1198, A-202,B-24),(IB-1199,A-203,B-24), (IB-1200,A-204,B-24), (IB-1201,A-205,B-24),(IB-1202,A-206,B-24), (IB-1203,A-207,B-24), (IB-1204,A-208,B-24),(IB-1205,A-209,B-24), (IB-1206,A-210,B-24), (IB-1207,A-211,B-24),(IB-1208,A-212,B-24), (IB-1209,A-213,B-24), (IB-1210,A-214,B-24),(IB-1211,A-215,B-24), (IB-1212,A-216,B-24), (IB-1213,A-217,B-24),(IB-1214,A-218,B-24), (IB-1215,A-219, B-24), (IB-1216,A-220,B-24),(IB-1217,A-221,B-24), (IB-1218,A-222,B-24), (IB-1219,A-223,B-24),(IB-1220,A-224,B-24), (IB-1221,A-225,B-24), (IB-1222,A-226,B-24),(IB-1223,A-227,B-24), (IB-1224,A-228,B-24), (IB-1225,A-229,B-24), (IB-1226,A-230,B-24), (IB-1227,A-231,B-24), (IB-1228,A-232,B-24),(IB-1229,A-233,B-24), (IB-1230,A-234,B-24), (IB-1231,A-235,B-24),(IB-1232,A-236,B-24), (IB-1233,A-237,B-24), (IB-1234,A-238,B-24),(IB-1235,A-239,B-24), (IB-1236, A-240;B-24), (IB-1237,A-241,B-24),(IB-1238,A-242,B-24), (IB-1239,A-243,B-24), (IB-1240,A-244,B-24),(IB-1241,A-245,B-24), (IB-1242,A-246,B-24), (IB-1243,A-247,B-24),(IB-1244,A-248,B-24), (IB-1245,A-249,B-24), (IB-1249,A-1,B-5),(IB-1250,A-1,B-6), (IB-1251,A-1,B-7), (IB-1252,A-1,B-8),(IB-1253,A-1,B-25), (IB-1254,A-1,B-26), (IB-1255,A-1,B-27),(IB-1256,A-1,B-28), (IB-1257,A-1,B-29), (IB-1258,A-1,B-30),(IB-1259,A-1,B-31), (IB-1260,A-1,B-32), (IB-1261,A-1, B-33),(IB-1262,A-1,B-34), (IB-1263,A-1,B-35), (IB-1264,A-1,B-36),(IB-1265,A-1,B-37), (IB-1266,A-1,B-38), (IB-1267,A-1,B-39),(IB-1268,A-1,B-40), (IB-1269, A-1,B-53), (IB-1270,A-1,B-54),(IB-1271,A-1,B-55), (IB-1272,A-1,B-56), (IB-1273,A-222,B-1),(IB-1274,A-222,B-3), (IB-1275,A-222,B-4), (IB-1276,A-222,B-5),(IB-1277,A-222,B-6), (IB-1278,A-222,B-7), (IB-1279,A-222,B-8),(IB-1280,A-222,B-25), (IB-1281,A-222,B-26), (IB-1282,A-222,B-27),(IB-1283,A-222,B-28), (IB-1284,A-222,B-29), (IB-1285,A-222,B-30),(IB-1286,A-222,B-31), (IB-1287,A-222,B-32), (IB-1288,A-222,B-33),(IB-1289,A-222,B-34), (IB-1290,A-222,B-35), (IB-1291,A-222,B-36),(IB-1292,A-222,B-37), (IB-1293,A-222,B-38), (IB-1294, A-222,B-39),(IB-1295,A-222,B-40), (IB-1296,A-222,B-53), (IB-1297,A-222,B-54),(IB-1298,A-222,B-55), (IB-1299,A-222,B-56), (IB-1300,A-225,B-1),(IB-1301, A-225,B-3), (IB-1302,A-225,B-4), (IB-1303,A-225,B-5),(IB-1304,A-225,B-6), (IB-1305,A-225,B-7), (IB-1306,A-225,B-8),(IB-1307,A-225,B-25), (IB-1308,A-225,B-26), (IB-1309,A-225,B-27),(IB-1310,A-225,B-28), (IB-1311,A-225,B-29), (IB-1312,A-225,B-30),(IB-1313,A-225,B-31), (IB-1314,A-225,B-32), (IB-1315,A-225,B-33),(IB-1316,A-225,B-34), (IB-1317,A-225,B-35), (IB-1318,A-225,B-36),(IB-1319,A-225,B-37), (IB-1320,A-225,B-38), (IB-1321,A-225,B-39),(IB-1322, A-225,B-40), (IB-1323,A-225,B-53), (IB-1324,A-225,B-54),(IB-1325,A-225,B-55), (IB-1326,A-225,B-56), (IB-1327,A-240,B-1),(IB-1328,A-240,B-3), (IB-1329, A-240,B-4), (IB-1330,A-240,B-5),(IB-1331,A-240,B-6), (IB-1332,A-240,B-7), (IB-1333,A-240,B-8),(IB-1334,A-240,B-25), (IB-1335,A-240,B-26), (IB-1336,A-240,B-27),(IB-1337,A-240,B-28), (IB-1338,A-240,B-29), (IB-1339,A-240,B-30),(IB-1340,A-240,B-31), (IB-1341,A-240,B-32), (IB-1342,A-240,B-33),(IB-1343, A-240,B-34), (IB-1344,A-240,B-35), (IB-1345,A-240,B-36),(IB-1346,A-240,B-37), (IB-1347,A-240,B-38), (IB-1348,A-240,B-39),(IB-1349,A-240,B-40), (IB-1350,A-240,B-53), (IB-1351,A-240,B-54),(IB-1352,A-240,B-55), (IB-1353,A-240,B-56), (IB-1354,A-241,B-1),(IB-1355,A-241,B-3), (IB-1356,A-241,B-4), (IB-1357, A-241,B-5),(IB-1358,A-241,B-6), (IB-1359,A-241,B-7), (IB-1360,A-241,B-8),(IB-1361,A-241,B-25), (IB-1362,A-241,B-26), (IB-1363,A-241,B-27),(IB-1364,A-241,B-28), (IB-1365,A-241,B-29), (IB-1366,A-241,B-30),(IB-1367,A-241,B-31), (IB-1368,A-241,B-32), (IB-1369,A-241,B-33),(IB-1370,A-241,B-34), (IB-1371, A-241,B-35), (IB-1372,A-241,B-36),(IB-1373,A-241,B-37), (IB-1374,A-241,B-38), (IB-1375,A-241,B-39),(IB-1376,A-241,B-40), (IB-1377,A-241,B-53), (IB-1378,A-241,B-54),(IB-1379,A-241,B-55), (IB-1380,A-241,B-56), (IB-1381,A-245,B-1),(IB-1382,A-245,B-3), (IB-1383,A-245,B-4), (IB-1384,A-245,B-5), (IB-1385,A-245,B-6), (IB-1386,A-245,B-7), (IB-1387,A-245,B-8),(IB-1388,A-245,B-25), (IB-1389,A-245,B-26), (IB-1390,A-245,B-27),(IB-1391,A-245,B-28), (IB-1392, A-245,B-29), (IB-1393,A-245,B-30),(IB-1394,A-245,B-31), (IB-1395,A-245,B-32), (IB-1396,A-245,B-33),(IB-1397,A-245,B-34), (IB-1398,A-245,B-35), (IB-1399,A-245,B-36),(IB-1400,A-245,B-37), (IB-1401,A-245,B-38), (IB-1402,A-245,B-39),(IB-1403,A-245,B-40), (IB-1404,A-245,B-53), (IB-1405,A-245,B-54),(IB-1406,A-245,B-55), (IB-1407,A-245,B-56), (IB-1408,A-250,B-2),(IB-1409,A-250, B-21), (IB-1410,A-250,B-22), (IB-1411,A-250,B-23),(IB-1412,A-250,B-24), (IB-1414,A-251,B-21), (IB-1415,A-251,B-22),(IB-1416,A-251,B-23), (IB-1417,A-251,B-24), (IB-1419,A-252,B-21),(IB-1420,A-252,B-22), (IB-1421,A-252,B-23), (IB-1422,A-252,B-24),(IB-1424,A-253,B-21), (IB-1425,A-253,B-22), (IB-1426,A-253,B-23),(IB-1427,A-253,B-24), (IB-1428,A-254,B-2), (IB-1429,A-254,B-21),(IB-1430,A-254,B-22), (IB-1431,A-254,B-23), (IB-1432,A-254,B-24),(IB-1433, A-255,B-2), (IB-1434,A-255,B-21), (IB-1435,A-255,B-22),(IB-1436,A-255,B-23), (IB-1437,A-255,B-24), (IB-1438,A-256,B-2),(IB-1439,A-256,B-21), (IB-1440, A-256,B-22), (IB-1441,A-256,B-23),(IB-1442,A-256,B-24), (IB-1443,A-257,B-2), (IB-1444,A-257,B-21),(IB-1445,A-257,B-22), (IB-1446,A-257,B-23), (IB-1447,A-257,B-24),(IB-1448,A-258,B-2), (IB-1449,A-258,B-21), (IB-1450,A-258,B-22),(IB-1451,A-258,B-23), (IB-1452,A-258,B-24), (IB-1453,A-259,B-2),(IB-1454,A-260,B-2), (IB-1455,A-261,B-2), (IB-1456,A-262,B-2),(IB-1457,A-263,B-2), (IB-1458,A-264,B-2), (IB-1459,A-265,B-2),(IB-1460,A-266,B-2), (IB-1461,A-267,B-2), (IB-1462,A-268,B-2),(IB-1463,A-269,B-2), (IB-1464,A-270,B-2), (IB-1465,A-271,B-2),(IB-1466,A-272,B-2), (IB-1467,A-273,B-2), (IB-1468,A-274,B-2),(IB-1469,A-275,B-2), (IB-1470,A-276,B-2), (IB-1471,A-277,B-2),(IB-1472,A-278,B-2), (IB-1473,A-279,B-2), (IB-1474,A-280,B-2),(IB-1475,A-281,B-2), (IB-1476,A-282,B-2), (IB-1477,A-283,B-2),(IB-1478,A-284,B-2), (IB-1479,A-285,B-2), (IB-1480,A-286,B-2),(IB-1481,A-287,B-2), (IB-1482,A-288,B-2)

Moreover, compounds of the next formula (IC):

wherein the ring A is 3-pyridyl, 2-furyl, 2-thienyl, 2-oxazolyl,2-thiazolyl, 2-benzoxazolyl, or 2-benzothiazolyl;

R^(3B) is a hydrogen atom, a bromine atom, methyloxy, ethyloxy,methylamino, 2-thiazolyl, a chlorine atom, methyl, amino, acetylamino,acetyl, N-methylcarbamoyl, phenyl, 4-fluorophenyl, 2-pyridyl, 3-pyridyl,2-oxazolyl, pyrrolidino, t-butyloxycarbonylamino, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 5-oxazolyl, a fluorine atom, phenoxy, cyano,nitro, carbamoyl, N-n-propylcarbamoyl, N-phenylcarbamoyl,methyloxycarbonylamino, i-propyloxycarbonylamino,3-pyridylcarbonylamino, 2-furylcarbonylamino, 3-methyloxyphenyl,4-methyloxyphenyl, 4-cyanophenyl, 4-oxazolyl, 5-methyl-2-oxazolyl,3,4-oxadiazol-2-yl, 5-methyl-3,4-oxadiazol-2-yl, 3,4-thiadiazol-2-yl,5-methyl-3,4-thiadiazol-2-yl, 4-pyridyl, 4-methyloxy-3-pyridyl,hydrazinocarbonyl, 3,4-methylenedioxyphenyl, N-cyclopropylcarbamoyl,4-isooxazolylcarbonylamino, 5-methyl-4-isooxazolylacrbonylamino,trifluoromethyl, or 3-methyloxypropargyl;

R^(6B) is a hydrogen atom or isopropoxy;

R^(7E) is independently a fluorine atom, a chlorine atom or methyl;

q is 0 or 1;

can be synthesized in the same manner as set forth above.

Compounds of the formula (IC) are shown below; (No. of the compound,R^(3B), A(R^(6B))(R^(7e))_(q)), (IC-1,H,4-F-6-isopropyloxy-3-pyridyl),(IC-2,H, 2-furyl), (IC-3,H,5-Me-2-furyl), (IC-4,H,2-thienyl),(IC-5,H,5-Me-2-thienyl), (IC-6,H,2-oxazolyl), (IC-7,H,5-methyl-2-oxazolyl), (IC-8,H,4-F-2-oxazolyl),(IC-9,H,4-isopropyloxy-2-oxazolyl), (IC-10,H,5-methyl-2-thiazolyl),(IC-11,H,4-F-2-thiazolyl), (IC-12,H,4-isopropyloxy-2-thiazolyl),(IC-13,H,5-F-2-benzoxazolyl), (IC-14,H,5-Cl-2-benzoxazolyl),(IC-15,H,5-Me-2-benzoxazolyl), (IC-16,H,5-isopropyloxy-2-benzoxazolyl),(IC-17,H,5-F-2-benzothiazolyl), (IC-18,H,5-Cl-2-benzothiazolyl),(IC-19,H,5-Me-2-benzothiazolyl),(IC-20,H,5-isopropyloxy-2-benzothiazolyl),(IC-21,Br,6-isopropyloxy-3-pyridyl),(IC-22,Br,4-F-6-isopropyloxy-3-pyridyl), (IC-23,Br,2-furyl),(IC-24,Br,5-Me-2-furyl), (IC-25,Br,2-thienyl),(IC-26,Br,5-Me-2-thienyl), (IC-27,Br,2-oxazolyl),(IC-28,Br,5-methyl-2-oxazolyl), (IC-29,Br,4-F-2-oxazolyl),(IC-30,Br,4-isopropyloxy-2-oxazolyl), (IC-31,Br,5-methyl-2-thiazolyl),(IC-32,Br,4-F-2-thiazolyl), (IC-33,Br,4-isopropyloxy-2-thiazolyl),(IC-34,Br,5-F-2-benzoxazolyl), (IC-35,Br,5-Cl-2-benzoxazolyl),(IC-36,Br,5-Me-2-benzoxazolyl),(IC-37,Br,5-isopropyloxy-2-benzoxazolyl),(IC-38,Br,5-F-2-benzothiazolyl), (IC-39,Br,5-Cl-2-benzothiazolyl),(IC-40,Br,5-Me-2-benzothiazolyl),(IC-41,Br,5-isopropyloxy-2-benzothiazolyl),(IC-42,OMe,6-isopropyloxy-3-pyridyl),(IC-43,OMe,4-F-6-isopropyloxy-3-pyridyl), (IC-44,OMe,2-furyl), (IC-45,OMe,5-Me-2-furyl), (IC-46,OMe,2-thienyl), (IC-47,OMe,5-Me-2-thienyl),(IC-48, OMe,2-oxazolyl), (IC-49,OMe,5-methyl-2-oxazolyl),(IC-50,OMe,4-F-2-oxazolyl), (IC-51,OMe,4-isopropyloxy-2-oxazolyl),(IC-52,OMe,5-methyl-2-thiazolyl), (IC-53,OMe,4-F-2-thiazolyl),(IC-54,OMe,4-isopropyloxy-2-thiazolyl), (IC-55,OMe,5-F-2-benzoxazolyl),(IC-56,OMe,5-Cl-2-benzoxazolyl), (IC-57,OMe,5-Me-2-benzoxazolyl),(IC-58,OMe,5-isopropyloxy-2-benzoxazolyl),(IC-59,OMe,5-F-2-benzothiazolyl), (IC-60,OMe,5-Cl-2-benzothiazolyl),(IC-61,OMe,5-Me-2-benzothiazolyl),(IC-62,OMe,5-isopropyloxy-2-benzothiazolyl),(IC-63,OEt,6-isopropyloxy-3-pyridyl),(IC-64,OEt,4-F-6-isopropyloxy-3-pyridyl), (IC-65,OEt,2-furyl),(IC-66,OEt,5-Me-2-furyl), (IC-67,OEt,2-thienyl),(IC-68,OEt,5-Me-2-thienyl), (IC-69,OEt,2-oxazolyl),(IC-70,OEt,5-methyl-2-oxazolyl), (IC-71,OEt,4-F-2-oxazolyl),(IC-72,OEt,4-isopropyloxy-2-oxazolyl), (IC-73,OEt,5-methyl-2-thiazolyl),(IC-74,OEt,4-F-2-thiazolyl), (IC-75,OEt,4-isopropyloxy-2-thiazolyl),(IC-76,OEt,5-F-2-benzoxazolyl), (IC-77,OEt,5-Cl-2-benzoxazolyl),(IC-78,OEt,5-Me-2-benzoxazolyl),(IC-79,OEt,5-isopropyloxy-2-benzoxazolyl),(IC-80,OEt,5-F-2-benzothiazolyl), (IC-81,OEt,5-Cl-2-benzothiazolyl),(IC-82,OEt,5-Me-2-benzothiazolyl),(IC-83,OEt,5-isopropyloxy-2-benzothiazolyl),(IC-84,NHMe,6-iisopropyloxy-3-pyridyl),(IC-85,NHMe,4-F-6-isopropyloxy-3-pyridyl), (IC-86,NHMe,2-furyl),(IC-87,NHMe,5-Me-2-furyl), (IC-88,NHMe,2-thienyl),(IC-89,NHMe,5-Me-2-thienyl), (IC-90,NHMe,2-oxazolyl),(IC-91,NHMe,5-methyl-2-oxazolyl), (IC-92,NHMe, 4-F-2-oxazolyl),(IC-93,NHMe,4-isopropyloxy-2-oxazolyl),(IC-94,NHMe,5-methyl-2-thiazolyl), (IC-95,NHMe,4-F-2-thiazolyl),(IC-96,NHMe,4-isopropyloxy-2-thiazolyl),(IC-97,NHMe,5-F-2-benzoxazolyl), (IC-98,NHMe,5-Cl-2-benzoxazolyl),(IC-99,NHMe,5-Me-2-benzoxazolyl),(IC-100,NHMe,5-isopropyloxy-2-benzoxazolyl),(IC-101,NHMe,5-F-2-benzothiazolyl), (IC-102,NHMe,5-Cl-2-benzothiazolyl),(IC-103,NHMe,5-Me-2-benzothiazolyl),(IC-104,NHMe,5-isopropyloxy-2-benzothiazolyl),(IC-105,2-thiazolyl,6-isopropyloxy-3-pyridyl),(IC-106,2-thiazolyl,74-F-6-isopropyloxy-3-pyridyl),(IC-107,2-thiazolyl,2-furyl), (IC-108,2-thiazolyl,5-Me-2-furyl),(IC-109,2-thiazolyl,2-thienyl), (IC-110,2-thiazolyl,5-Me-2-thienyl),(IC-111,2-thiazolyl,2-oxazolyl),(IC-112,2-thiazolyl,5-methyl-2-oxazolyl),(IC-113,2-thiazolyl,4-F-2-oxazolyl),(IC-114,2-thiazolyl,4-isopropyloxy-2-oxazolyl),(IC-115,2-thiazolyl,5-methyl-2-thiazolyl),(IC-116,2-thiazolyl,4-F-2-thiazolyl),(IC-117,2-thiazolyl,4-isopropyloxy-2-thiazolyl),(IC-118,2-thiazolyl,5-F-2-benzoxazolyl),(IC-119,2-thiazolyl,5-Cl-2-benzoxazolyl),(IC-120,2-thiazolyl,5-Me-2-benzoxazolyl),(IC-121,2-thiazolyl,5-isopropyloxy-2-benzoxazolyl),(IC-122,2-thiazolyl,5-F-2-benzothiazolyl),(IC-123,2-thiazolyl,5-Cl-2-benzothiazolyl),(IC-124,2-thiazolyl,5-Me-2-benzothiazolyl),(IC-125,2-thiazolyl,5-isopropyloxy-2-benzothiazolyl),(IC-126,Cl,6-isopropyloxy-3-pyridyl),(IC-127,Me,6-isopropyloxy-3-pyridyl),(IC-128,NH2,6-isopropyloxy-3-pyridyl),(IC-129,NHAc,6-isopropyloxy-3-pyridyl),(IC-130,Ac,6-isopropyloxy-3-pyridyl),(IC-131,CONHMe,6-isopropyloxy-3-pyridyl),(IC-132,Ph,6-isopropyloxy-3-pyridyl),(IC-133,4-F-phenyl,6-isopropyloxy-3-pyridyl),(IC-134,2-pyridyl,6-isopropyloxy-3-pyridyl), (IC-135,3-pyridyl,6-isopropyloxy-3-pyridyl),(IC-136,2-oxazolyl,6-isopropyloxy-3-pyridyl),(IC-137,pyrrolidino,6-isopropyloxy-3-pyridyl),(IC-138,NHBoc,6-isopropyloxy-3-pyridyl),(IC-139,2-furyl,6-isopropyloxy-3-pyridyl),(IC-140,3-furyl,6-isopropyloxy-3-pyridyl),(IC-141,2-thienyl,6-isopropyloxy-3-pyridyl),(IC-142,3-thienyl,6-isopropyloxy-3-pyridyl),(IC-143,5-oxazolyl,6-isopropyloxy-3-pyridyl),(IC-144,F,6-isopropyloxy-3-pyridyl),(IC-145,OPh,6-isopropyloxy-3-pyridyl),(IC-146,CN,6-isopropyloxy-3-pyridyl),(IC-147,NO2,6-isopropyloxy-3-pyridyl),(IC-148,CONH2,6-isopropyloxy-3-pyridyl),(IC-149,CONHn-Pr,6-isopropyloxy-3-pyridyl),(IC-150,CONHPh,6-isopropyloxy-3-pyridyl), (IC-151,NHCOOMe,6-isopropyloxy-3-pyridyl),(IC-152,NHCOOi-Pr,6-isopropyloxy-3-pyridyl), (IC-153,NHCO(3-pyridyl),(6-isopropyloxy-3-pyridyl), (IC-154,NHCO(2-furyl),(6-isopropyloxy-3-pyridyl),(IC-155,3-methyloxyphenyl,6-isopropyloxy-3-pyridyl),(IC-156,4-methyloxyphenyl,6-isopropyloxy-3-pyridyl),(IC-157,4-cyanophenyl,6-isopropyloxy-3-pyridyl),(IC-158,4-oxazolyl,6-isopropyloxy-3-pyridyl),(IC-159,5-Me-2-oxazolyl,6-isopropyloxy-3-pyridyl),(IC-160,3,4-oxadiazol-2-yl,6-isopropyloxy-3-pyridyl),(IC-161,5-Me-3,4-oxadiazol-2-yl,6-isopropyloxy-3-pyridyl),(IC-162,3,4-thiadiazol-2-yl,6-isopropyloxy-3-pyridyl),(IC-163,5-Me-3,4-thiadiazol-2-yl,6-isopropyloxy-3-pyridyl),(IC-164,4-pyridyl,6-isopropyloxy-3-pyridyl),(IC-165,4-methyloxy-3-pyridyl,6-isopropyloxy-3-pyridyl),(IC-166,CONHNH2,6-isopropyloxy-3-pyridyl),(IC-167,1-pyrazolyl,6-isopropyloxy-3-pyridyl),(IC-168,3,4-methylenedioxyphenyl,6-isopropyloxy-3-pyridyl),(IC-169,CONH(cyclopropyl), (6-isopropyloxy-3-pyridyl),(IC-170,NHCO(4-isoxazolyl), (6-isopropyloxy-3-pyridyl),(IC-171,NHCO(5-Me-isoxazol-3-yl), (6-isopropyloxy-3-pyridyl),(IC-172,CF3,6-isopropyloxy-3-pyridyl),(IC-173,3-methyloxypropargyl,6-isopropyloxy-3-pyridyl),(IC-174,2-methyloxyethyloxy,6-isopropyloxy-3-pyridyl), (IC-175,benzyloxy,6-isopropyloxy-3-pyridyl),(IC-176,3-furylmethyloxy,6-isopropyloxy-3-pyridyl),(IC-177,2-oxopyrrolidino,6-isopropyloxy-3-pyridyl).

Test Example 1 DP Inhibitory Activity In Vitro

1) Preparation of Platelet and a Method of cAMP Assay

30 ml of peripheral blood was collected from a healthy volunteer using asyringe containing one ninth amount of 3.8% sodium citrate fordiagnosis. After being centrifuged at 180 g for 10 minutes at roomtemperature, a supernatant was collected and used as Platelet RichPlasma (PRP). The resulting PRP was washed with wash buffer andcentrifuged three times (Washed Platelet: WP) and platelets were countedby a microcell counter. WP was added to a plate in amount of1.5×10⁸/assay and the plate was treated with 3-isobutyl-1-methylxanthin(IBMX; 0.5 mM) for 5 minutes. A reaction was initiated by adding 100 nMof PGD₂ 5 min after an addition of a test compound. The reaction wasterminated with an addition of 1N hydrochloric acid after 2 minutes andthe cells were destructed using 12% triton X-100. An amount of cAMP inthe supernatant was assayed by Homogeneous Trangient Fluorescence (HTRF)

2) Receptor Binding Assay

A prepared WP was homogenated and a membrane fraction was collected withhigh-speed centrifugation. A compound of the present invention or areference compound A (No. IC-73 in WO 2003/097598) was added to theplate and [³H]-PGD₂ was also added. A platelet membrane, a proteinconcentration is 2 mg/mL, was added and mixed in the plate, and placedon ice for 2 hours. The reaction solution was transferred to a lowprotein-adsorptive filter and washed with a wash solution eight timesusing a cell harvester. After the final washing, water was removedsufficiently, and microscint was added. DP inhibitory activity wasinvestigated by measuring [³H] by using Micro Beta.

50% DP-inhibitory concentrations (IC50) in the cAMP assay and Ki valuesin the receptor binding assay were shown in Table 29.

3) Prostanoid Agonist and Antagonist Assay

Agonistic and antagonistic activities of the compounds of the presentinvention were evaluated based on intracellular calcium flux orcAMP-production as an indicator using HEK 293 cells expressing humanEP1, EP2, EP3, EP4, FP, TP and IP respectively. Any compounds did notshow an agonistic activity against each prostanoid. In the other hand,more than twenty times potent antagonistic activity (IC₅₀) was found inevery compound compared with IC₅₀ of cAMP assay with WP.

[Table 38]

compound IC₅₀ Ki No. (nM) (nM) I-1  0.58 1.0 I-6  0.93 1.0 I-12 1.6 0.91I-13 0.51 0.85 I-14 0.33 0.61 I-16 0.64 I-17 0.88 0.25 Reference 23Compound A I-19 2.2 I-20 0.64 0.48 I-21 1.9 0.51 I-25 1.1 I-26 1.7 I-291.5 I-31 1.7

Test Example 2 Test Using OVA Asthma Model of Rat

Brown Norway (BN) Rats were sensitized by i.p. administration of 0.1mg/mL of ovalbumin (OVA) and 1 mg of aluminum hydroxide gel. A solutionof 1% OVA was aerosolized by ultrasonic nebulizer (NE-U17) and the ratswere subjected to inhalation exposure of the aerosol for 30 minutes inan exposing chamber 12, 19, 26 and 33 days after the sensitization. Onehour before the 4th exposure of the antigen, compounds of the presentinvention were administered in a dose of 10 mg/kg p.o. once a day forthree days consecutively. In a control group, 0.5% of methyl cellulosewas administered in place of the compound of the present invention.

Under pentobarbital anesthesia (80 mg/kg, i.p.), acetylcholine (3.9,7.8, 15.6, 31.3, 62.5, 125, 250 and 500 μg/kg) was injected to jugularvein of the rats successively from a lower dose at intervals of 5minutes three days after the fourth exposure to the antigen, andimmediate contractile reaction of airways (an increase of insufflationpressure) was measured by a modified method of Konnzett & Rössler.Inhibition rate of increased hyperresponsive airway against the controlgroup was calculated based on area under curve (AUC) obtained fromconcentration-response curve of acetylcholine.

After the measurement of increased hyperresponsive airway was completed,bronchoalveoli of the rats were washed with 5 mL of saline three times.Total cell number in the washings was counted by a hemacytometer underlight microscope, and inhibition rates of infiltration of inflammatorycells against the control group were calculated. Further, muchin in theairway lavage fluid was measured by ELIZA method using jacalin, amuchin-binding lectin, and the inhibition rates of mucus-secretionagainst the control group were calculated.

Results were shown in Table 39.

TABLE 39 inhibition rate (%) increased infiltration of compound dosehyperresponsive inflammatory mucus- No. (mg/kg) airway cells secretionI-1 10 55 63 68 I-6 10 69 60 77 I-12 10 64 48 55 I-13 10 58 62 44 I-1410 84 68 88

Test Example 3 Test Using Nasal Congestion Model of Guinea Pig

Methods of measuring nasal airway resistance and evaluating anti-nasalcongestion activity using a rat were illustrated below.

A 1% solution of ovalbumin (OVA) was aerosolized by ultrasonicnebulizer, a male Hartley guinea pigs was sensitized by inhalation ofthe aerosol for 10 minutes twice at an interval of a week and a reactionwas initiated by exposure to the antigen 7 days later. Trachea of theguinea pig was incised under pentobarbital anesthesia (30 mg/kg, i.p.),and cannulae were fitted at the sides of nasal cavity and lungrespectively. To the lung side, a ventilator supplying 4 mL of air everytime at a rate of 60 times/min was connected. Spontaneous breathing ofthe guinea pig was stopped by the administration of gallamine (2 mg/kg,i.v.) and 4 mL of air every time was supplied at a rate of 70times/minute to rostrum of nose through the cannula of the nasal sideusing a ventilator. Air pressure necessary for supplying the air wasmeasured by a transducer fitted at the side branch and used as anindicator for resistance of nasal cavity. Exposure to the antigen wasperformed by generating the aerosol of 3% OVA solution between theventilator and the nasal cavity cannula for three minutes. Compounds ofthe present invention were administered intravenously 10 minutes beforethe exposure to the antigen. Resistance of nasal cavity was continuouslymeasured during a period from 0 to 30 minutes, and the inhibition rateagainst the vehicle was obtained based on AUC of the 30 minutes, whichwas recorded with resistance of nasal cavity (cm H₂O) as a longitudinalaxis, and time (from 0 to 30 min.) as an abscissa axis.

FORMULATION EXAMPLE

The following formulating examples are just for illustrative purposesand not intended to limit the range of the present invention. A term of“active ingredient” means the compounds of the present invention,pharmaceutically acceptable salt or hydrate thereof.

Formulation Example 1

A hard-gelatin capsule is prepared with the following ingredients;

Amount (mg/capsule) active ingredient 250 starch (dried) 200 magnesiumstearate 10 Total 460 mg

Formulation Example 2

A tablet is prepared with the following ingredients;

Amount (mg/tablet) active ingredient 250 cellulose(micro crystalline)400 silicon dioxide (fume) 10 stearic acid 5 Total 665 mgThe ingredients above are mixed and compressed to give a tablet weighing665 mg/tablet.

Formulation Example 3

An aerosol solution is prepared with the following ingredients;

weight active ingredient 0.25 ethanol 25.75 propellant22(chlorodifluoroethane) 74.00 Total 100.00

The active ingredient and ethanol are mixed and the mixture is added toa part of propellant 22, and the resulting solution is transferred to afilling apparatus after being cooled to −30° C. Next, the necessaryamount is provided to a stainless-steel vessel and the content isdiluted with the remaining propellant. A valve unit is fitted to thevessel.

Formulation Example 4

A tablet containing 60 mg of an active ingredient is prepared asfollows;

active ingredient 60 mg starch 45 mg macrocrystalline cellulose 35 mgpolyvinylpyrrolidone (10% aq. solution) 4 mg sodium carboxymethylstarch4.5 mg magnesium stearate 0.5 mg talc 1 mg Total 150 mg

The active ingredient, starch and cellulose are put through a sieve ofNo. 45 mesh US and mixed sufficiently. The resulting powder is mixedwith a solution containing polyvinylpyrrolidone and the mixture is putthrough a sieve of No. 14 mesh US. The granulated powder is dried at 50°C. and put through a sieve of No. 18 mesh US. Sodiumcarboxymethylstarch, magnesium stearate and talc are put through a sieveof No. 60 mesh US in advance and added to the granulated powder, mixedand compressed by a tableting machine to give a tablet weighing 150mg/tablet.

Formulation Example 5

A capsule containing 80 mg of an active ingredient is prepared asfollows;

active ingredient 80 mg starch 59 mg microcrystalline cellulose 59 mgmagnesium stearate 2 mg Total 200 mg

The active ingredient, starch, cellulose and magnesium stearate aremixed, put through a sieve of No. 45 mesh US and filled in hard-gelatincapsules to give a capsule formulation containing 200 mg/capsule.

Formulation Example 6

A suppository containing 225 mg of an active ingredient is prepared asfollows;

active ingredient 225 mg saturated fatty acid gliceride 2000 mg Total2225 mg

The active ingredient is put through a sieve of No. 60 mesh US andsuspended in the saturated fatty acid glyceride melted by the leastamount of heating. Then, the mixture was cooled in a mold of 2 g inappearance.

Formulation Example 7

A suspension containing 50 mg of an active ingredient is prepared asfollows;

active ingredient 50 mg sodium carboxymethylcellulose 50 mg syrup 1.25ml solution of benzoic acid 0.10 ml flavor q.v. pigment q.v. Total(adding purified water) 5 ml

The active ingredient is put through a sieve of No. 45 mesh US and mixedwith sodium carboxymethylcellulose and syrup to give a smooth paste. Thesolution of benzoic acid and flavor are diluted with a part of water andadded to the paste and stirred. A necessary amount of water is added togive the objective suspension.

Formulation Example 8

A formulation for i.v. injection is prepared as follows;

active ingredient 100 mg saturated fatty acid gliceride 1000 ml

The solution containing the active ingredient above is usually injectedintravenously to a patient at a rate of 1 ml/min.

INDUSTRIAL APPLICABILITY

It was found that a novel indole derivative had a DP receptorantagonistic activity and was effective on treating allergic diseases.

1. A compound of the general formula (II):

wherein the ring C is a formula of

the formula of —X¹═X²—X³═X⁴— is a formula of _(v)—C(R¹)═C(R²)—C(R³)═N—;R¹, R², R³ and R⁵ are independently a hydrogen atom, halogen atom,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, hydroxy, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,optionally substituted cycloalkyloxy, optionally substitutedcycloalkenyloxy, mercapto, optionally substituted alkylthio, optionallysubstituted alkenylthio, optionally substituted alkynylthio, optionallysubstituted alkylsulfonyl, optionally substituted alkylsulfonyl,optionally substituted alkylsulfonyloxy, optionally substitutedcycloalkylthio, optionally substituted cycloalkylsulfinyl, optionallysubstituted cycloalkylsulfonyl, optionally substitutedcycloalkylsulfonyloxy, optionally substituted cycloalkenylthio,optionally substituted cycloalkenylsulfinyl, optionally substitutedcycloalkenylsulfonyl, optionally substituted cycloalkenylsulfonyloxy,optionally substituted amino, acyl, optionally substitutedalkyloxycarbonyl, optionally substituted alkenyloxycarbonyl, optionallysubstituted alkynyloxycarbonyl, optionally substituted carbamoyl,optionally substituted sulfamoyl, cyano, nitro, optionally substitutedaryl, optionally substituted aryloxy, optionally substituted arylthio,optionally substituted arylsulfonyl, optionally substitutedarylsulfonyl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, optionallysubstituted heteroarylthio, optionally substituted heteroarylsulfinyl,optionally substituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or optionally substituted non-aromaticheterocyclic group; R¹² is optionally substituted C1-C6 alkyloxy,optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6alkynyloxy, optionally substituted C1-C6 alkylthio, optionallysubstituted C2-C6 alkenylthio, optionally substituted C2-C6 alkynylthio,optionally substituted C3-C6 cycloalkyloxy, optionally substituted C3-C6cycloalkylthio, optionally substituted aryloxy or optionally substitutedarylthio; R¹³ is independently a halogen atom, optionally substitutedalkyl, optionally substituted cycloalkyl, optionally substituted amino,acyl, optionally substituted alkyloxycarbonyl, optionally substitutedcarbamoyl, optionally substituted sulfamoyl, cyano, nitro, optionallysubstituted aryl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl or optionally substituted non-aromaticheterocyclic group; R¹⁴ is independently optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, oxo,optionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted non-aromatic heterocyclic group; M is carbonyl orsulfoyl; Y and L⁴ are independently a single bond or optionallysubstituted alkylene optionally containing one or two heteroatom(s); Zis CH, C(R¹³) or N; n is 0, 1 or 2; and q is 0, 1, 2or 3; or apharmaceutically acceptable salt thereof.
 2. A compound of the generalformula (III):

wherein the ring D is a formula of

R¹⁵, R¹⁶ and R¹⁸ are independently a hydrogen atom, a halogen atom,optionally substituted alkyl, optionally substituted alkyloxy,optionally substituted alkylthio, optionally substituted alkylsulfinyl,optionally substituted alkylsulfonyl, optionally substituted amino,cyano, nitro, optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted non-aromatic heterocyclic group;R¹⁷ is independently a hydrogen atom, a halogen atom, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cyloalkyl, optionallysubstituted cyloalkenyl, hydroxy, optionally substituted alkyloxy,optionally substituted alkenyloxy, optionally substituted alkynyloxy,mercapto, optionally substituted alkylthio, optionally substitutedalkenylthio, optionally substituted alkynylthio, optionally substitutedalkylsulfinyl, optionally substituted alkynylsulfonyl, optionallysubstituted alkynylsulfonyloxy, optionally substituted amino, acyl,optionally substituted alkyloxycarbonyl, optionally substitutedalkenyloxycarbonyl, optionally substituted alkynyloxycarbonyl,optionally substituted carbamoyl, optionally substituted sulfamoyl,cyano, nitro, optionally substituted aryl, optionally substitutedaryloxy, optionally substituted arylthio, optionally substitutedarylsulfonyl, optionally substituted arylsulfonyl, optionallysubstituted arylsulfonyloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheteroarylthio, optionally substituted heteroarylsulfinyl, optionallysubstituted heteroarylsulfonyl, optionally substitutedheteroarylsulfonyloxy, or an optionally substituted non-aromaticheterocyclic group; R¹⁹ is optionally substituted C1-C6 alkyloxy,optionally substituted C2-C6 alkenyloxy, optionally substituted C2-C6alkynyloxy, optionally substituted C1-C6 alkylthio, optionallysubstituted C2-C6 alkenylthio, optionally substituted C2-C6 alkynylthio,optionally substituted C3-C6 cycloalkyloxy, optionally substituted C3-C6cycloalkylthio, optionally substituted aryloxy or optionally substitutedarylthio; R²⁰ is independently a halogen atom, optionally substitutedalkyl, optionally substituted cyloalkyl, optionally substituted amino,acyl, optionally substituted alkyloxycarbonyl, optionally substitutedcarbamoyl, optionally substituted sulfamoyl, cyano, nitro, optionallysubstituted aryl, optionally substituted arylsulfonyloxy, optionallysubstituted heteroaryl or an optionally substituted non-aromaticheterocyclic group; R²¹ is independently optionally substituted alkyl,optionally substituted alkenyl, optionally substituted alkynyl, oxo,optionally substituted aryl, optionally substituted heteroaryl, or anoptionally substituted non-aromatic heterocyclic group; M is carbonyl orsulfonyl; Z is CH, C(R²⁰), or N; n is 0, 1 or 2 and q is 0, 1, 2or 3; ora pharmaceutically acceptable salt thereof.
 3. A compound of claim 2wherein R¹⁷ is a hydrogen atom, a halogen atom, optionally substitutedalkyl, optionally substituted alkyloxy, optionally substituted amino,optionally substituted carbamoyl, optionally substituted aryl,optionally substituted heteroaryl or an optionally substitutednon-aromatic heterocyclic ring; or a pharmaceutically acceptable saltthereof.
 4. A compound of claim 2 wherein R¹⁵, R¹⁶ and R¹⁸ are hydrogenatoms, or a pharmaceutically acceptable salt thereof.
 5. A compound ofclaim 2 wherein R¹⁹ is optionally substituted C1-C6 alkyl or optionallysubstituted C1-C6 alkylthio, or a pharmaceutically acceptable saltthereof.
 6. A compound of claim 2 wherein R²⁰ is a halogen atom,optionally substituted alkyl or optionally substituted alkyloxy, and qis 0 or 1, or a pharmaceutically acceptable salt thereof.
 7. A compoundof claim 2 wherein M is sulfonyl, or a pharmaceutically acceptable saltthereof.
 8. A compound of any of claim 2-7 wherein R²¹ is alkyl or oxo,and n is 0, or a pharmaceutically acceptable salt thereof.
 9. Apharmaceutical composition comprising the compound or claim 1 or 2, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 10. A method for inhibiting DP receptor whichcomprises administering the compound of claim 1 or 2, or apharmaceutically acceptable salt thereof, to a patient in need thereof.11. A method of treating asthma which comprises administering thecompound of claim 1 or 2, or a pharmaceutically acceptable salt thereof,to a patient in need thereof.